(19) United States (12) Patent Application Publication (10 ... · distribution) for a spray-dried...

(19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0051473 A1

Farrow et al.

US 2016.0051473A1

(43) Pub. Date: Feb. 25, 2016

(54) TAURINE COMPOSITIONS SUITABLE FOR NHALATION

(71) Applicant: VECTURA LIMITED, Chippenham, Wiltshire (GB)

(72) Inventors: David Farrow, Wiltshire (GB); Katie Coggins, Wiltshire (GB)

(21) Appl. No.: 14/779,156

(22) PCT Filed: Mar. 26, 2014

(86). PCT No.: PCT/GB14/SO953

S371 (c)(1), (2) Date: Sep. 22, 2015

(30) Foreign Application Priority Data

Mar. 28, 2013 (GB) ................................... 1305813.6

Publication Classification

(51) Int. Cl. A619/16 (2006.01) A6II 45/06 (2006.01) A613 L/40 (2006.01) A619/00 (2006.01) A63L/85 (2006.01)

(52) U.S. Cl. CPC ............... A61K 9/1617 (2013.01); A61 K9/008

(2013.01); A61 K3I/I85 (2013.01); A61 K 31/40 (2013.01); A61K 45/06 (2013.01); A61 K

9/1682 (2013.01) (57) ABSTRACT The invention discloses spray-dried compositions for inhala tion and methods for preparing Such powder compositions. The compositions of the invention are produced by spray drying taurine under conditions that (i) retain the physical and chemical stability of the composition during spray drying and upon storage, (ii) protect the powder composition from aggre gation and (iii) provide particles Suitable for aerosolisation.

Patent Application Publication Feb. 25, 2016 Sheet 1 of 10 US 2016/0051473 A1

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US 2016/005 1473 A1

TAURINE COMPOSITIONS SUITABLE FOR NHALATION

0001. The present invention relates to stable materials, compositions comprising such materials suitable for inhala tion and methods for preparing Such compositions.

BACKGROUND OF THE INVENTION

0002 The process of spray drying has been widely used in the production of pharmaceuticals since the 1940s (Corrigan, 1995). The food industry also commonly employs spray dry ing to produce food products demonstrating enhanced Stabil ity and suitable for long term storage (Sliwinski et al., 2004). Spray drying is a one step process used to convert a liquid based feedstock (Such as a solution, Suspension or emulsion) into a dried powder form by atomizing the feedstock in drop lets, into a hot drying-medium, typically air or nitrogen. The process provides enhanced control over particle size, size distribution, particle shape, density, purity and structure. As formulators are able to control these parameters so precisely, spray drying as a possible method for formulating dry powder compositions intended for pulmonary delivery has also been investigated in recent years (WO 96/32194). 0003 Spray drying active pharmaceutical ingredients (API) or biological material suitable for inhalation normally requires the presence of stabilizing excipients and/or diluents. 0004. The de-facto spray drying excipient of choice is often Mannitol as it possesses many advantageous properties. Mannitol will readily dry in a crystalline state, is water soluble and is considered non-hygroscopic as it picks up less than 1% moisture at relative humidity as high as 70% (Hand book of Pharmaceutical Excipients, 6' Edition, R. C. Rowe). In addition it can pick up 10% of mass in water at humidity’s >70% RH. However despite mannitol's attractive stabilizing capabilities, it is a tussive agent and will induce coughing when administered via the pulmonary route. 0005. As an alternative choice excipient, trehalose is often used for spray drying compositions. Trehalose (C-D-glu copyranosyl-O-D-glucopyranoside) is a naturally occurring, non-reducing disaccharide which was initially found to be associated with the prevention of desiccation damage in cer tain plants and animals which can dry out without damage and can revive when rehydrated. Trehalose however does not spray dry completely crystalline and will instead form an amorphous matrix. This amorphous matrix is hygroscopic and will readily absorb water. Spray-dried trehalose therefore Suffers from physical stability issues, principally particle agglomeration, resulting in loss of primary particle size and aerosol performance characteristics. 0006 Thus a need still exists for materials such as excipi ents for preparing stable inhalable compositions which exhibit excellent aerosolisation properties and demonstrate very low levels of agglomeration. Ideally, Such excipients will spray dry in a crystalline form and will possess various favourable attributes such as low toxicity (with no cough induced side effects), low hygroscopicity, high melting point, with very low moisture content (advantageous for long term storage).

SUMMARY OF THE INVENTION

0007. The invention relates to a method for preparing con ditioned taurine, the method comprising a conditioning step, optionally a spray drying step, to produce taurine that:

Feb. 25, 2016

(a) demonstrates no significant net change in the Doo (t20%) after 7 days of ambient storage; and (b) have a particle size (Do) of <20 um, but more preferably <10 um after 7 days of ambient storage, optionally and preferably in which a method Zwitterionic neutralisation is facilitated during spray drying of the taurine. 0008. The invention also relates to conditioned taurine, obtained or obtainable by the method of the invention and to a composition comprising conditioned taurine, Such as a dry powder composition Suitable for inhalation. 0009. The invention further relates to a method for prepar ing conditioned taurine the method comprising drying solu bilised taurine, optionally by spray drying with one or more of the following parameters: (a) the pH of the feedstock to be spray dried is acidic e.g. less than pH 5, preferably equal to or less then pH 4, such as about pH 4; (b) wherein the feedstock concentration is between 0.1% and 10%, more preferably between 1% and 5%; (c) the feedstock temperature is between 0.1° C. and 100°C., more preferably between 20° C. and 70° C.: (d) the outlettemperature is between 50° C. and 120°C., more preferably between 60° C. and 100° C.: (e) the Test ratio is between 2.000x10 and 2.750x10 3.

0010. The invention also relates to a container comprising: 0.011 (a) conditioned taurine; or 0012 (b) a composition comprising conditioned tau rine.

0013 The invention also relates to a method for preparing conditioned taurine, the method being a multi-step process, in one embodiment a two-step process, and in one further embodiment a one step process Such as spay drying.

FIGURES

0014 FIG. 1 is a response plot of modelled residual results versus actual data. The boxed area highlights the 8 condi tioned taurine batches. (0015 FIG. 2 is a variability chart showing how the 8 conditioned taurine batches span the whole theoretical oper ating range for spray dryers. The conditioned taurine batches are shown as a function of the Ten ratios. 0016 FIG. 3 is a plot showing the relationship of condi tioned taurine batches which obey a quadratic relationship with the Do of the PSD after 7 days (R=0 0.91 Prob>F 0.0031). 0017 FIG. 4 is a TGA (thermo-gravimetric analysis) graph depicting the weight loss mean as a percentage at the initial time point, T=0 for 24 samples of spray-dried taurine. 0018 FIG. 5 is a TGA (thermo-gravimetric analysis) graph depicting the weight loss mean as a percentage at the 7 day time point, T-7 days for 24 samples of spray-dried tau 1.

0019 FIG. 6 is a DSC (differential scanning calorimetry) graph depicting a sample of spray-dried taurine. (0020 FIG. 7 depicts the pKa profile of taurine. 0021 FIG. 8 depicts the pH profile and isoelectric point of taurine. 0022 FIG. 9 lists the joint factor tests indicating signifi cance of all variables. 0023 FIG. 10 is a graph depicting the PSD (particle size distribution) for a spray-dried trehalose/leucine/salbutamol powder composition obtained by spray-drying under Process A conditions where T=0.

US 2016/005 1473 A1

0024 FIG. 11 is a graph depicting the PSD (particle size distribution) for a spray-dried trehalose/leucine/salbutamol powder composition obtained by spray-drying under Process A, stored under ambient sealed conditions where T-24 hours. 0025 FIG. 12 is a graph depicting the PSD (particle size distribution) for a spray-dried taurine/leucine/salbutamol powder composition obtained by spray-drying under Process B conditions where T=0. 0026 FIG. 13 is a graph depicting the PSD (particle size distribution) for a spray-dried taurine/leucine/salbutamol powder composition obtained by spray-drying under Process B, stored under ambient sealed conditions where T-24 hours. 0027 FIG. 14 is a graph depicting the PSD (particle size distribution) for a spray-dried trehalose/leucine/salbutamol powder composition obtained by spray-drying under Process B conditions where T=0. 0028 FIG. 15 is a graph depicting the PSD (particle size distribution) for a spray-dried trehalose/leucine/salbutamol powder composition obtained by spray-drying under Process B, stored under ambient sealed conditions where T-24 hours. 0029 FIG. 16 is a graph depicting the PSD (particle size distribution) for a spray-dried taurine/leucine/salbutamol powder composition obtained by spray-drying under Process B, stored open at 25°C/50% RH, where T-24 hours.

DETAILED DESCRIPTION OF THE INVENTION

0030 Taurine or 2-aminoethanesulfonic acid is an organic acid that is ubiquitous in the human body, constituting 0.1% w/w of its total weight (EFSA Response Letter, EFSA-Q- 2007-113, 2009). It has been shown to be tolerable in excess of 1000 mg kg day' by the EFSA with no indications of inhalation toxicity or intolerability. Taurine has exceptionally low moisture sorption characteristics and is thus considered non-hygroscopic as it does not take up any water at a relative humidity of between 0% and 100%. It is also soluble in water, is not considered a tussive agent and when spray-dried, pro duces particles with very low moisture content (less than 1% w/w, more preferably less than 0.5% w/w). 0031 Taurine is a versatile molecule with various impor tant biological functions, including: antioxidation; conjuga tion of bile acids; modulation of calcium signalling: osmo regulation and membrane stabilization. Taurine is also regularly used as a dietary Supplement and as an ingredient in energy drinks. 0032. Although there is little evidence in the literature of taurine being utilised as an active pharmaceutical ingredient, it has been described for the treatment of cardiac failure, and a taurine based composition has been disclosed in the treat ment of asthma and various other respiratory failures (WO 92/17170). In the latter example, the taurine based composi tion was administered by pulmonary inhalation as an aeroso lised solution. 0033 Spray drying taurine to create inhalable taurine par

ticles that do not agglomerate has proven Surprisingly chal lenging. 0034. In the present invention we have determined spray drying taurine under certain conditions can result in particle agglomeration over 1 to 7 days resulting in a loss of primary particles and negligible aerosol performance. 0035 However, under certain conditions taurine can be produced which is suitable for inhalation use, and does not display Such agglomeration. Such taurine is referred to as conditioned taurine herein, and in one aspect is made by the methods of the invention as disclosed herein, although other

Feb. 25, 2016

methods can be used. Conditioned taurine is suitably taurine that demonstrates no significant net change in the Doo (t20%) after 7 days of ambient storage and has a particle size (Do) of <20 um, but more preferably <10 um after 7 days of ambient Storage. 0036 Provided herein is also a likely basis for the agglom eration of taurine which permits conditioned taurine to be produced by spray drying and other methods, the basis referred to herein as the Zwitterionic neutralisation theory.

DEFINITIONS

0037. It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. Those skilled in the art will recognise, or be able to ascertain using no more than routine study, numerous equivalents to the specific proce dures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims. 0038. The term “Taurine' is intended to encompass salt forms or counterion formulations of taurine as well as iso lated Stereoisomers (e.g. D-Taurine or L-Taurine) and mix tures of stereoisomers. Derivatives and intermediates of tau rine (e.g. hypotaurine) are also encompassed. 0039. The term “Raw Taurine” refers to commercially available pure taurine. 0040. The term “Processed Taurine' refers to taurine that has been spray-dried using spray drying conditions with resulting taurine particles tending to agglomerate (i.e. dem onstrate a net change in the Do (>20%) after 7 days of ambient storage) and have a particle size (Do) of >20 um after 7 days of ambient storage. 0041. The term “Conditioned Taurine' refers to taurine that has been prepared to obtain taurine particles that demon strate very low levels of agglomeration (i.e. demonstrate no significant net change in the Doo (t20%) after 7 days of ambient storage) and remain as aerosolisable primary par ticles e.g. where particles have aparticle size (Do) of <20um, but more preferably <10 um after 7 days of ambient storage. 0042. The term “Leucine' is intended to encompass salt forms or counterion formulations of leucine as well as iso lated Stereoisomers (e.g. D-Leucine or L-Leucine) and mix tures of stereoisomers. Derivatives and intermediates of leu cine are also encompassed. 0043. The term 'Agglomerate' or 'Agglomeration” refers to the process whereby particles cohere to one another to create particle clusters, which demonstrate larger particle dimensions.

0044. The term “Aerosolised or “Aerosolisable” refers to particles, which when dispensed from a dry powder inhala tion device, will remain Suspended in the inhaler's gas stream for an amount of time suitable for at least a portion of the particles to be inhaled by the patient, thereby reaching the patients lungs. 0045. The term “Process Parameters' refers specifically to spray drying parameters such as: drying gas flow rate; atomi sation gas flow rate; feedstock pumping rate; outlet tempera ture, feedstock temperature; feedstock concentration and feedstock pH and buffer?acid type. 0046. The term “Do” refers to the size in microns below which 10% of the particles reside on a volume basis.

US 2016/005 1473 A1

0047. The term “Dso refers to the size in microns above or below which 50% of the particles reside on a volume basis. 0048. The term “Do” refers to the size in microns below which 90% of the particles reside on a volume basis. 0049. The term "Inhalation” or “Inhalable” refers to par ticles that are suitable for pulmonary administration. Such particles typically have a mean aerodynamic particle size of less than 10 Jum, more preferably less than 5 um and most preferably less than 3.5 Lum. 0050. The term “Process A' refers to a preferred spray drying process for producing optimal trehalose particles Suit able for inhalation using in one embodiment the Niro spray dryer. 0051. The term “Process B” refers to a preferred spray drying process for producing optimal taurine particles, namely conditioned taurine particles Suitable for inhalation using in one embodiment the Niro spray dryer. 0052. The term “Ambient Conditions' refers to material sealed and stored at room temperature at about 20°C.2.0°C. in the laboratory. 0053. The term “Medicament” refers to pharmaceutical active agents or bioactive material. Medicament may also refer to combinations of pharmaceutical agents, combina tions of bioactive material or combinations of pharmaceutical agent and bioactive material. 0054) The term “Container” refers to either a bulk storage container, Such as a multi-dose reservoir for a dry powder inhaler, or unit dose containers such as a capsule or ablister. The capsule may be formed from various materials e.g. gelatine, cellulose derivatives such as hydroxypropyl meth ylcellulose (HPMC) or hydroxypropylcellulose (HPC), starch, starch derivatives, chitosan or synthetic plastics, while the blister may be provided in the form of a blister pack or blister strip. 0055. The term “Passive Device” refers to a dry powder inhaler device in which a patient’s breathe is the only source of gas which provides the motive force in the device. 0056. The term “Active Device” refers to a dry powder inhaler device in which a source of compressed gas or an alternative energy source is used to provide the motive force in the device. 0057 The term “Glass Transition Temperature', which is represented by the symbol T refers to the temperature at which a composition changes from a glassy or vitreous state to a syrup or rubbery state. T is generally determined using differential scanning calorimetry (DSC). I0058. The term “T, ratio” refers to the mass of taurine per Volume of drying gas per unit time in the spray dryer.

General Statements

0059. As used in this specification and the claim(s), the use of the word “a” or “an' when used in conjunction with the term "comprising in the claim(s) and/or the specification may mean 'one', but it is also consistent with the meaning of “one or more', 'at least one', and “one or more than one'. The use of the term “or” in the claim(s) is used to mean “and/or unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure Supports a definition that refers to only alternatives and “and/or”. 0060. As used in this specification and claim(s), the words “comprising (and any form of comprising, Such as "com prise' and "comprises”), “having (and any form of having,

Feb. 25, 2016

such as “have and “has'), “including' (and any form of including, such as “includes and “include’) or “containing (and any form of containing, such as “contains and “con tain’) are inclusive or open-ended and do not exclude addi tional, unrecited elements or method steps. 0061 The term “any combinations thereofas used herein refers to all permutations and mixtures of the listed items preceding the term. For example, "A, B, C, or any combina tions thereofisintended to include at least one of A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are mix tures that contain repeats of one or more items or terms. Such as BB, AAA, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there 525 is no limit on the number of items or terms in any mixture, unless otherwise apparent from the context. 0062 All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publi cations and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indi cated to be incorporated by reference.

Detailed Description

Process

0063. The invention relates to, inter alia, a method for preparingtaurine, the method comprising a conditioning step, wherein taurine is produced in the form of particles that: (a) demonstrate no significant net change in the Doo (t20%) after 7 days of ambient storage; and (b) have a particle size (Do) of <20 um, but more preferably <10 um after 7 days of ambient storage, optionally and preferably in which a method Zwitterionic neutralisation is facilitated during drying of the taurine. 0064. As taurine is a Zwitterionic compound, it is believed that the Sulphur-hydyl group of the taurine becomes ionised (oxidation) with the proton being added to the amine group (reduction), in the feedstock of a spray drying approach, and retains a charge even after drying. This leads to the material relaxing on storage which is believed to be the charged groups neutralising resulting in a conformatorial structural change. This conformatorial change causes agglomeration of the par ticles in the dry state, leading to a significant reduction in the aerosol performance. It is believed the neutralisation has a vitrification intermediate phase, which is the cause of the agglomeration. 0065. In one aspect facilitation of Zwitterionic neutralisa tion is the prevention or minimising of ionic interaction between the sulphur-hydyl group of the taurine and the amine group, Such as the use of conditions that minimise or prevent reduction of the amine group and/or oxidation of the Sulphur hydyl group. 0.066 Further, we have demonstrated in the examples herein that predictive models can be generated that allow modulation of the spray drying parameters consistent with this theory to allow conditioned taurine as defined hereinto be produced. 0067 Parameters that affect the Zwitterionic neutralisa tion process include:

0068 Drying Gas flow rate 0069. Atomisation gas flow rate

US 2016/005 1473 A1

0070 Feedstock pumping rate (0071. Outlet temperature (0072. Feedstock temperature 0073. Feedstock concentration (0074 Feedstock pH and buffer/acid type

0075 Thus in one aspect of the invention any one or more of the above parameters may be varied to allow conditioned taurine to be produced, and the invention relates to a method for spray drying taurine, wherein one or more or all of these properties are controlled to produce conditioned taurine, optionally wherein a model using one or more or all param eters is used to predict appropriate parameters for the produc tion of conditioned taurine.

0076. In one embodiment of the invention the taurine is spray dried. 0077. In one embodiment of the invention the pH of the feedstock to be spray dried is acidic e.g. less than pH 5 in one embodiment equal to or less then pH 4. Such as about pH 4. 0078. In a further aspect of the invention the feedstock concentration is between 0.1% and 10%, in one embodiment between 1% and 5%.

0079. In another aspect of the invention the feedstock tem perature is between 0.1° C. and 100° C., in one embodiment between 20° C. and 70° C.

0080. In still a further aspect of the invention the outlet temperature is between 50° C. and 120° C., in one embodi ment between 60° C. and 100° C.

0081. In another aspect of the invention the T is between 2.000x10 and 2.750x10. 0082. The production of conditioned taurine can be con firmed by:

(Solidigas) rat1O

(a) no significant net change in the Do (t20%) after 7 days of ambient storage; and (b) a particle size (Do) of <20 um, but more preferably <10 um after 7 days of ambient storage following the drying process.

0083. In a further aspect of the invention raw commer cially available taurine may be comminuted to reduce particle size before any processing to produce conditioned taurine as described herein. Particle size reduction is preferably to form a particle of size less than 20 Lum in diameter, in one embodi ment less than 10 um in diameter. 0084 Comminution can be achieved through various pro cesses in isolation, for example media milling or jet milling (micronisation). 0085 Conditioning is the process of allowing charge neu

tralisation induced, for example following the communition step. I0086 For the avoidance of doubt the conditioning of tau rine may be carried out by spray drying but other techniques may also be used to produce conditioned taurine. Such as fluid bed conditioning. Fluid bed conditioning is considered a one step conditioning process but would additionally require a separate comminution step and so a preferred method to achieve both the conditioned step and the comminution step simultaneously, repeatably and more economically is to use spray drying. 0087. The method of preparing conditioned taurine may therefore involve a multi-step process, or in one embodiment a two-step process or in one further embodiment a one-step process Such as spray drying.

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I0088 Spray drying solubilises the taurine raw material and produces Smaller particles through atomisation, which in this sense, due to the size reduction, is considered as commi nuted. I0089. In a further aspect of the present invention, the con ditioned taurine is made by a spray drying method compris ing: providing a feedstock comprising raw taurine in an aque ous solution or Suspension, and spray drying the feedstock under conditions to create particles that demonstrate no sig nificant net change in the Do (+20%) after 7 days of ambient storage; and have a particle size (Do) of <20 m, but more preferably <10 um after 7 days of ambient storage.

Product

0090. The invention relates to conditioned taurine obtained or obtainable using the method of the invention, and to compositions comprising Such taurine perse. 0091 For example, the invention relates to a composition comprising conditioned taurine, such as a dry powder com position suitable for inhalation. 0092. In one embodiment the conditioned taurine is sub stantially in crystalline form, with at least 95% of the taurine or more having a crystalline form 0093. In one embodiment of the invention, the conditioned taurine is present in an amount less than 99.9% by weight based on the dry weight of the composition e.g. less than 98.5%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 2.5% by weight based on the dry weight of the composition. 0094. Inafurther embodiment of the invention, taurine has a moisture content of less than 2% by weight, optionally less than 1% by weight, optionally less than 0.5% by weight of conditioned taurine.

Compositions and Other Elements

0095. In another embodiment of the present invention, the conditioned taurine is both Suitable for use as, and for use as an excipient, carrier or diluent in a pharmaceutical composi tion.

0096. The taurine of the invention may be prepared in combination with other components, such as drugs or excipi ents, for example in a co-spray dried process. 0097. In one embodiment the taurine may be dried, e.g. co-spray dried with leucine in an aqueous Solution or Suspen Sion, wherein the aqueous solution or Suspension is spray dried under conditions to produce a composition comprising conditioned taurine and leucine Suitable for inhalation. 0098. In one embodiment the spray-dried composition comprising leucine will comprise leucine present in an amount less than 10% by weight based on the dry weight of the composition e.g. less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, in one embodiment less than 4%, in one embodiment less than 3%, in one embodiment less than 2% by weight based on the dry weight of the composition. 0099. In a further in one embodiment of the present inven tion, a composition comprising taurine may also comprise an additive material Such as a so-called force control agent. A force control agent is an agent which reduces the cohesion between fine particles within the powder composition. Suit able force control agents include amino acids, metal Stearates Such as magnesium Stearate, phospholipids, lecithin, colloi

US 2016/005 1473 A1

dal silicon dioxide and sodium Stearyl fumarate. In one embodiment the force control agent is magnesium Stearate. 0100 Amino acids which are suitable for use in the present invention include alanine, leucine, isoleucine, lysine, Valine, methionine or phenylalanine. In one embodiment the amino acid is leucine. The inclusion of these amino acids improves the aerosol performance of the composition. 0101. In yet a further embodiment of the present invention, the amino acid, in one embodiment leucine, is present in an amount less than 10% by weight based on the dry weight of the composition e.g. less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, in one embodiment less than 4%, in one embodiment less than 3%, in one embodiment less than 2% by weight based on the dry weight of the composition. 0102. In still a further embodiment of the present inven

tion, the amino acid is predominately present on the Surface of the conditioned taurine. Without wishing to be bound by theory this may result from the amino acid's hydrophobic and Surface active properties.

Actives

0103) In yet a further aspect of the present invention, the composition further comprises a medicament or a combina tion of medicaments selected from the following: 1) Adrenergic agonists such as, for example, amphetamine, apraclonidine, bitolterol, clonidine, colterol, dobutamine, dopamine, ephedrine, epinephrine, ethylnorepinephrine, fenoterol, formoterol, guanabenz, guanfacine, hydroxyam phetamine, isoetharine, isoproterenol, isotharine, mephenter ine, metaraminol, methamphetamine, methoxamine, meth pentermine, methyldopa, methylphenidate, metaproterenol, metaraminol, mitodrine, naphazoline, norepinephrine, oxymetazoline, pemoline, phenylephrine, phenylethylamine, phenylpropanolamine, pirbuterol, prenalterol, procaterol, propylhexedrine, pseudoephedrine, ritodrine, salbutamol. salmeterol, terbutaline, tetrahydrozoline, tramaZoline, tyramine and Xylometazoline. 2) Adrenergic antagonists such as, for example, acebutolol. alfuzosin, atenolol, betaxolol, bisoprolol, bopindolol, bucin dolol, bunaZosin, butyrophenones, carteolol, carvedilol. celiprolol, chlorpromazine, doxazosin, ergot alkaloids, esmolol, haloperidol, indoramin, ketanserin, labetalol, levobunolol, medroxalol, metipranolol, metoprolol, nebiv olol, nadolol, naftopidil, Oxprenolol, penbutolol, phenothiaz ines, phenoxybenzamine, phentolamine, pindolol, praZosin, propafenone, propranolol, Sotalol, tamsulosin, teraZosin, timolol, tolazoline, trimaZosin, urapidil and yohimbine. 3) Adrenergic neurone blockers such as, for example, bethanidine, debrisoquine, guabenXan, guanadrel, guanaZo dine, guanethidine, guanoclor and guanoxan. 4) Drugs for treatment of addiction, such as, for example, buprenorphine. 5) Drugs for treatment of alcoholism, such as, for example, disulfiram, naloxone and naltrexone. 6) Drugs for Alzheimer's disease management, including acetylcholinesterase inhibitors such as, for example, done pezil, galantamine, rivastigmine and tacrin. 7) Anaesthetics Such as, for example amethocaine, ben Zocaine, bupivacaine, hydrocortisone, ketamine, lignocaine, methylprednisolone, prilocaine, proxymetacaine, ropiv acaine and tyrothricin. 8) Angiotensin converting enzyme inhibitors such as, for example, captopril, cilaZapril, enalapril, fosinopril, imidapril

Feb. 25, 2016

hydrochloride, lisinopril, moexipril hydrochloride, perin dopril, quinapril, ramipril and trandolapril. 9)Angiotensin receptor blockers, such as, for example, can desartan, cilexetil, eprosartan, irbesartan, losartan, medox omil, olmesartan, telmisartan and Valsartan. 10) Antiarrhythmics such as, for example, adenosine, amido darone, disopyramide, flecainide acetate, lidocaine hydro chloride, mexiletine, procainamide, propafenone and quini dine. 11) Antibiotic and antibacterial agents (including the beta lactams, fluoroquinolones, ketolides, macrollides, Sulphona mides and tetracyclines) Such as, for example, aclarubicin, amoxicillin, amphotericin, azithromycin, aztreonam chlo rhexidine, clarithromycin, clindamycin, colistimethate, dac tinomycin, dirithromycin, doripenem, erythromycin, fusafungine, gentamycin, metronidazole, mupirocin, nata mycin, neomycin, nyStatin, oleandomycin, pentamidine, pimaricin, probenecid, roXithromycin, Sulphadiazine and tri closan. 12) Anti-clotting agents such as, for example, abciximab, acenocoumarol, alteplase, aspirin, bemiparin, bivalirudin, certoparin, clopidogrel, dalteparin, danaparoid, dipy ridamole, enoxaparin, epoprostenol, eptifibatide, fondaparin, heparin (including low molecular weight heparin), heparin calcium, lepirudin, phenindione, reteplase, Streptokinase, tenecteplase, tinzaparin, tirofiban and warfarin. 13) Anticonvulsants such as, for example, GABA analogs including tiagabine and vigabatrin; barbiturates including pentobarbital; benzodiazepines including alprazolam, chlor diazepoxide, clobazam, clonazepam, diazepam, flurazepam, lorazepam, midazolam, oxazepam and Zolazepam, hydanto ins including phenytoin: phenyltriazines including lamot rigine; and miscellaneous anticonvulsants including aceta Zolamide, carbamazepine, ethoSuximide, fosphenytoin, gabapentin, levetiracetam, oXcarbazepine, piracetam, pre gabalin, primidone, sodium valproate, topiramate, Valproic acid and Zonisamide. 14) Antidepressants such as, for example, tricyclic and tetra cyclic antidepressants including amineptine, amitriptyline (tricyclic and tetracyclic amitryptiline), amoxapine, butrip tyline, cianopramine, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, do Sulepin, dothiepin, doxepin, imipramine, iprindole, levoprotiline, lofepramine, maprotiline, melitracen, metapramine, mianserin, mirtazap ine, nortryptiline, opipramol, propizepine, protriptyline, quinupramine, Setiptiline, tianeptine and trimipramine; selec tive serotonin and noradrenaline reuptake inhibitors (SNRIs) including clovoxamine, dulloxetine, milnacipran and ven lafaxine; selective serotonin reuptake inhibitors (SSRIs) including citalopram, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, milnacipran, nomifensine, Oxapro tiline, paroxetine, Sertraline, Sibutramine, Venlafaxine, Vidua line and Zimeldine; selective noradrenaline reuptake inhibi tors (NARIS) including demexiptiline, desipramine, oxaprotiline and reboxetine; noradrenaline and selective serotonin reuptake inhibitors (NASSAs) including mirtazap ine; monoamine oxidase inhibitors (MAOIs) including ami flamine, brofaromine, clorgyline, a-ethyltryptamine, etoperi done, iproclozide, iproniazid, isocarboxazid, mebanazine, medifoxamine, moclobemide, nialamide, pargyline, phenelZine, pheniprazine, pirlindole, procarbazine, rasa giline, Safrazine, selegiline, toloxatone and tranylcypromine; muscarinic antagonists including benactyzine and diben Zepin; azaspirones including buspirone, gepirone, ipsapirone,

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tandospirone and tiaspirone; and other antidepressants including acetaphenazine, ademetionine, S-adenosylme thionine, adrafinil, ameSergide, amineptine, amperozide, benactyzine, benmoxine, binedaline, bupropion, carbam azepine, caroXaZone, cericlamine, cotinine, fezolamine, flu pentixol. idazoxan, kitanserin, levoprotiline, lithium salts, maprotiline, medifoxamine, methylphenidate, metralindole, minaprine, nefazodone, nisoxetine, nomifensine, oxafloZane, oxitriptan, phenyhydrazine, rolipram, roXindole, Sibutra mine, teniloxazine, tianeptine, tofenacin, traZadone, tryp tophan, Viloxazine and Zalospirone. 15) Anticholinetgic agents such as, for example, atropine, benZatropine, biperiden, cyclopentolate, glycopyrrolate, hyoscine, ipratropium bromide, orphenadine hydrochloride, oxitroprium bromide, oxybutinin, pirenzepine, procyclidine, propantheline, propiverine, telenzepine, tiotropium, trihex yphenidyl, tropicamide and trospium. 16) Antidiabetic agents such as, for example, pioglitaZone, rosiglitaZone and troglitaZone. 17) Antidotes such as, for example, deferoxamine, edropho nium chloride, fiumazenil, nalmefene, naloxone, and naltrex OC.

18) Anti-emetics such as, for example, alizapride, azasetron, benzquinamide, bestahistine, bromopride, buclizine, chlor promazine, cinnarizine, clebopride, cyclizine, dimenhydri nate, diphenhydramine, diphenidol, domperidone, dolas etron, dronabinol, droperidol, granisetron, hyoscine, lorazepam, metoclopramide, metopimazine, nabilone, ondansetron, palonosetron, perphenazine, prochlorperazine, promethazine, Scopolamine, triethylperazine, trifluopera Zine, triflupromazine, trimethobenzamide and tropisetron. 19) Antihistamines such as, for example, acrivastine, astemi Zole, azatadine, azelastine, brompheniramine, carbinoxam ine, cetirizine, chlorpheniramine, cinnarizine, clemastine, cyclizine, cyproheptadine, desloratadine, dexmedetomidine, diphenhydramine, doxylamine, fexofenadine, hydroxy Zine, ketotifen, levocabastine, loratadine, mizolastine, promethaZ ine, pyrilamine, terfenadine and trimeprazine. 20) Anti-infective agents such as, for example, antivirals (in cluding nucleoside and non-nucleoside reverse transcriptase inhibitors and protease inhibitors) including aciclovir, ade fovir, amantadine, cidofovir, efavirenz, famiciclovir, foscar net, ganciclovir, idoxuridine, indinavir, inosine pranobex, lamivudine, nelfinavir, nevirapine, oseltamivir, palivizumab, penciclovir, pleconaril, ribavirin, rimantadine, ritonavir, ruprintrivir, saquinavir, stavudine, Valaciclovir, Zalcitabine, Zanamivir, Zidovudine and interferons: AIDS adjunct agents including dapsone; aminoglycosides including tobramycin; antifungals including amphotericin, caspofungin, clotrima Zole, econazole nitrate, fluconazole, itraconazole, ketocona Zole, miconazole, nystatin, terbinafine and Voriconazole; anti-malarial agents including quinine; antituberculosis agents including capreomycin, ciprofloxacin, ethambutol, meropenem, piperacillin, rifampicin and Vancomycin; beta lactams including cefazolin, cefimetazole, cefoperaZone, cefoxitin, cephacetrile, cephalexin, cephaloglycin and cepha loridine; cephalosporins, including cephalosporin C and cephalothin; cephamycins such as cephamycin A, cephamy cin, cephamycin C, cephapirin and cephradine; leprostatics Such as clofazimine; penicillins including amoxicillin, ampi cillin, amylpenicillin, azidocillin, benzylpenicillin, carbeni cillin, carfecillin, carindacillin, clometocillin, cloxacillin, cyclacillin, dicloxacillin, diphenicillin, heptylpenicillin, het acillin, metampicillin, methicillin, nafcillin, 2-pentenylpeni

Feb. 25, 2016

cillin, penicillin N, penicillin 0, penicillin S and penicillin V: quinolones including ciprofloxacin, clinafloxacin, difloxacin, grepafloxacin, norfloxacin, ofloxacine and temafloxacin, tet racyclines including doxycycline and oxytetracycline; mis cellaneous anti-infectives including lineZolide, trimethoprim and Sulfamethoxazole. 21) Anti-neoplastic agents such as, for example, droloxifene, tainoxifen and toremifene. 22) Antiparkisonian drugs such as, for example, amantadine, andropinirole, apomorphine, baclofen, benserazide, biperiden, benztropine, bromocriptine, budipine, caber goline, carbidopa, eliprodil, entacapone, eptastigmine, ergoline, galanthamine, lazabemide, levodopa, lisuride, mazindol, memantine, mofegiline, orphenadrine, trihex yphenidyl, pergolide, piribedil, pramipexole, procyclidine, propentofylline, rasagiline, remacemide, ropinerole, sel egiline, spheramine, terguride and tolcapone. 23) Antipsychotics such as, for example, acetophenazine, alizapride, amisulpride, amoxapine, amperozide, aripipra Zole, benperidol, benzquinamide, bromperidol, buramate, butaclamol, butaperazine, carphenazine, carpipramine, chlo rpromazine, chlorprothixene, clocapramine, clomacran, clo penthixol, clospirazine, clothiapine, clozapine, cyame mazine, droperidol, flupenthixol, fluiphenazine, fluspirilene, haloperidol, loxapine, melperone, mesoridazine, metofenazate, molindrone, olanzapine, penfluridol, peri cyazine, perphenazine, pimozide, pipamerone, piperac etazine, pipotiazine, prochlorperazine, promazine, quetiap ine, remoxipride, risperidone, sertindole, spiperone, Sulpiride, thioridazine, thiothixene, trifluperidol, triflupro mazine, trifluoperazine, Ziprasidone, Zotepine and Zuclo penthixol; phenothiazines including aliphatic compounds, piperidines and piperazines; thioxanthenes, butyrophenones and substituted benzamides. 24) Antirheumatic agents such as, for example, diclofenac, heparinoid, hydroxychloroquine and methotrexate, lefluno mide and teriflunomide. 25) Anxiolytics such as, for example, adinazolam, alpidem, alprazolam, alseroxlon, amphenidone, azacyclonol, bro mazepam, bromisovalum, buspirone, captodiamine, capu ride, carbcloral, carbromal, chloral betaine, chlordiazep oxide, clobenzepam, enciprazine, flesinoxan, flurazepam, hydroxy Zine, ipsapiraone, lesopitron, loprazolam, lorazepam, loxapine, mecloqualone, medetomidine, meth aqualone, methprylon, metomidate, midazolam, oxazepam, propanolol, tandospirone, traZadone, Zolpidem and Zopi clone. 26) Appetite stimulants such as, for example, dronabinol. 27) Appetite Suppressants such as, for example, fenfluramine, phentermine and Sibutramine; and anti-obesity treatments Such as, for example, pancreatic lipase inhibitors, serotonin and norepinephrine re-uptake inhibitors, and anti-anorectic agents. 28) BenZodiazepines such as, for example, alprazolam, bro mazepam, brotizolam, chlordiazepoxide, clobazam, clon azepam, cloraZepate, demoxepam, diazepam, estaZolam, flunitrazepam, flurazepam, halazepam, ketazolam, lopra Zolam, lorazepam, lormetazepam, medazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quaZepam, temazepam and triazolam. 29) Bisphosphonates such as, for example, alendronate Sodium, Sodium clodronate, etidronate disodium, ibandronic acid, pamidronate disodium, isedronate Sodium, tiludronic acid and Zoledronic acid.

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30) Blood modifiers such as, for example, cilostazol and dipyridamol, and blood factors. 31) Cardiovascular agents such as, for example, acebutalol, adenosine, amiloride, amiodarone, atenolol, benazepril, biso prolol, bumetanide, candesartan, captopril, clonidine, dilt iazem, disopyramide, dolfetilide, doxazosin, enalapril, esmolol, ethacrynic acid, flecanide, furosemide, gemfibrozil, ibutilide, irbesartan, labetolol, losartan, lovastatin, metola Zone, metoprolol, mexiletine, nadolol, nifedipine, pindolol. prazosin, procainamide, propafenone, propranolol, quinapril, quinidine, ramipril, Sotalol, Spironolactone, telmisartan, tocainide, torsemide, triamterene, Valsartan and Verapamil. 32) Calcium channel blockers such as, for example, amlo dipine, bepridil, diltiazem, felodipine, flunarizine, gallo pamil. isradipine, lacidipine, lercanidipine, nicardipine, nife dipine, nimodipine and Verapamil. 33) Central nervous system stimulants such as, for example, amphetamine, brucine, caffeine, dexfenfluramine, dextroam phetamine, ephedrine, fenfluramine, mazindol, methypheni date, modafmil, perinoline, phentermine and Sibutramine. 34) Cholesterol-lowering drugs such as, for example, acipi moX, atorvastatin, ciprofibrate, colestipol, colestyramine, bezafibrate, ezetimibe, fenofibrate, fluvastatin, gemfibrozil, ispaghula, nictotinic acid, omega-3 triglycerides, pravastatin, rosuvastatin and simvastatin. 35) Drugs for cystic fibrosis management such as, for example, Pseudomonas aeruginosa infection vaccines (eg AerugenTM), alpha 1-antitripsin, amikacin, cefadroxil, denu fosol, duramycin, glutathione, mannitol, and tobramycin. 36) Diagnostic agents such as, for example, adenosine and aminohippuric acid. 37) Dietary Supplements such as, for example, melatonin and Vitamins including vitamin E. 38) Diuretics such as, for example, amiloride, bendroflume thiazide, bumetanide, chlortalidone, cyclopenthiazide, furo semide, indapamide, metolaZone, Spironolactone and torasemide. 39) Dopamine agonists such as, for example, amantadine, apomorphine, bromocriptine, cabergoline, lisuride, per golide, pratnipexole and ropinerole. 40) Drugs for treating erectile dysfunction, such as, for example, apomorphine, apomorphine diacetate, moxisylyte, phentolamine, phosphodiesterase type 5 inhibitors, such as sildenafil, tadalafil. Vardenafil and yohimbine. 41) Gastrointestinal agents such as, for example, atropine, hyoscyamine, famotidine, lansoprazole, loperamide, ome prazole and rebeprazole. 42) Hormones and analogues such as, for example, cortisone, epinephrine, estradiol, insulin, Ostabolin-C, parathyroid hor mone and testosterone. 43) Hormonal drugs such as, for example, desmopressin, lanreotide, leuprolide, octreotide, pegvisomant, protirelin, salcotonin, Somatropin, tetracosactide, thyroxine and vaso pressin. 44) Hypoglycaemics such as, for example, Sulphonylureas including glibenclamide, gliclazide, glimepiride, glipizide and gliquidone; biguanides including metformin; thiazo lidinediones including pioglitaZone, rosiglitaZone, nateglin ide, repaglinide and acarbose.

45) Immunoglobulins.

0104 46) Immunomodulators such as, for example, inter feron (e.g. interferon beta-la and interferon beta-Ib) and glati a.

Feb. 25, 2016

47) Immunosupressives Such as, for example, azathioprine, cyclosporin, mycophenolic acid, rapamycin, sirolimus and tacrolimus. 48) Mast cell stabilizers such as, for example, cromoglycate, iodoxamide, nedocromil, ketotifen, tryptase inhibitors and pemirolast. 49) Drugs for treatment of migraine headaches such as, for example, almotriptan, alperopride, amitriptyline, amoxapine, atenolol, clonidine, codeine, coproxamol, cyproheptadine, dextropropoxypene, dihydroergotamine, diltiazem, doxepin, ergotamine, eletriptan, fluoxetine, froVatriptan, isomethep tene, lidocaine, lisinopril, lisuride, loxapine, methysergide, metoclopramide, metoprolol, nadolol, naratriptan, nortrip tyline, oxycodone, paroxetine, pizotifen, pizotyline, prochlo rperazine propanolol, propoxyphene, protriptyline, rizatrip tan, Sertraline, Sumatriptan, timolol, tolfenamic acid, tramadol, Verapamil, Zolmitriptan, and nonsteroidal anti-in flammatory drugs. 50) Drugs for treatment of motion sickness such as, for example, diphenhydramine, promethazine and Scopolamine. 51) Mucolytic agents such as N-acetylcysteine, ambroXol. amiloride, dextrans, heparin, desulphated heparin, low molecular weight heparin and recombinant human DNase. 52) Drugs for multiple Sclerosis management Such as, for example, bencyclane, methylprednisolone, mitoxantrone and prednisolone. 53) Muscle relaxants such as, for example, baclofen, chlor ZOxazone, cyclobenzaprine, methocarbamol, orphenadrine, quinine and tizanidine. 54) NMDA receptor antagonists such as, for example, mementine. 55) Nonsteroidal anti-inflammatory agents such as, for example, aceclofenac, acetaminophen, alminoprofen, amfenac, amin-prop-loanm, ixetrine, aspirin, benoxaprofen, bromfenac, bufeXamac, carprofen, celecoxib, choline, cin chophen, cinmetacin, clometacin, clopriac, diclofenac, diclofenac sodium, diflunisal, ethenZamide, etodolac, etori coxib, fenoprofen, flurbiprofen, ibuprofen, indomethacin, indoprofen, ketoprofen, ketorolac, loxoprofen, maZipredone, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, nimeSulide, parecoxib, phenylbutaZone, piroxi cam, pirprofen, rofecoxib, salicylate, Sulindac, tiaprofenic acid, tolfenamate, tolmetin and Valdecoxib. 56) Nucleic-acid medicines Such as, for example, oligonucle otides, decoy nucleotides, antisense nucleotides and other gene-based medicine molecules. 57) Opiates and opioids Such as, for example, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide; buprenorphine, butorphanol, carbiphene, cipra madol, clonitaZene, codeine, codeine phosphate, dextro moramide, dextropropoxyphene, diamorphine, dihydroco deine, dihydromorphine, diphenoxylate, dipipanone, fentanyl, hydromorphone, L-alpha acetyl methadol, levor phanol, lofentanil, loperamide, meperidine, meptazinol, methadone, metopon, morphine, nalbuphine, nalorphine, oxycodone, papaveretum, pentazocine, pethidine, phenaZo cine, pholcodeine, remifentanil, Sufentanil, tramadol, and combinations thereof with an anti-emetic. 58) Opthalmic preparations such as, for example, betaxolol and ketotifen. 59) Osteoporosis preparations such as, for example, alendr onate, estradiol, estropitate, raloxifene and risedronate. 60) Other analgesics such as, for example, apaZone, benzpip erylon, benzydamine, caffeine, cannabinoids, clonixin, etho

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heptazine, flupirtine, nefopam, orphenadrine, pentazocine, propacetamol and propoxyphene. 61) Other anti-inflammatory agents such as, for example, B-cell inhibitors, p38 MAP kinase inhibitors and TNF inhibi tOrS.

62) Phosphodiesterase inhibitors such as, for example, non specific phosphodiesterase inhibitors including theophylline, theobromine, IBMX, pentoxifylline and papaverine; phos phodiesterase type 3 inhibitors including bipyridines such as milrinone, amrinone and olprinone; imidazolones Such as piroXimone and enoXimone; imidazolines Such as imaZodan and 5-methyl-imaZodan; imidazo-quinoxalines; and dihydro pyridazinones such as indolidan and LY 1815 12 (5-(6-0-0- 1,4,5,6-tetrahydro-pyridazin-3-y-)-I,3-dihydro-indo-2- one); dihydroquinolinone compounds Such as cilostamide, cilostazol, and Vesnarinone; motapizone; phosphodiesterase type 4 inhibitors such as cilomilast, etazolate, rolipram, oglemilast, roflumilast, ONO 6126, tolafentrine and Zardav erine, and including quinazolinediones such as nitraquaZone and nitraduaZone analogs; Xanthine derivatives such as den bufylline and arofylline; tetrahydropyrimidones such as ati Zoram; and oxime carbamates Such as filaminast; and phos phodiesterase type 5 inhibitors including sildenafil. Zaprinast, Vardenafil, tadalafil, dipyridamole, and the compounds described in WO 01/19802, particularly (S)-2-(2-hydroxym ethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)- 5N-(2-pyrimidinyl methyl)carbamoylpyrimidine, 2-(5,6,7, 8-tetrahydro-1.7-naphthyridin-7-yl)-4-(3-chloro-4- methoxybenzylamino)-5-N-(2-morpholinoethyl) carbamoyl-pyrimidine, and (S)-2-(2-hydroxymethyl-1- pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)-5-N-(I, 3,5-trimethyl-4-pyrazolyl)carbamoyl-pyrimidine). 63) Potassium channel modulators such as, for example, cro makalim, diazoxide, glibenclamide, levcromakalim, minoxi dil, nicorandil and pinacidil. 64) Prostaglandins such as, for example, alprostadil, dinopro stone, epoprostanol and misoprostol. 65) Respiratory agents and agents for the treatment of respi ratory diseases including bronchodilators such as, for example, the B2-agonists bambuterol, bitolterol, broxaterol, carmoterol, clenbuterol, fenoterol, formoterol, Vilanterol, indacaterol, levalbuterol, metaproterenol, orciprenaline, picumeterol, pirbuterol, procaterol, reproterol, rimiterol, salbutamol, salmeterol, terbutaline and the like; inducible nitric oxide synthase (iNOS) inhibitors; the antimuscarinics ipratropium, ipratropium bromide, OXitropium, tiotropium, glycopyrrolate and the like; the Xanthines aminophylline, theophylline and the like; adenosine receptor antagonists, cytokines such as, for example, interleukins and interferons; cytokine antagonists and chemokine antagonists including cytokine synthesis inhibitors, endothelin receptor antago nists, elastase inhibitors, integrin inhibitors, leukotrine recep tor antagonists, prostacyclin analogues, and ablukast, ephe drine, epinephrine, fenleuton, iloprost, iralukast, isoetharine, isoproterenol, montelukast, ontazolast, pranlukast, pseu doephedrine, sibenadet, tepoxalin, Verlukast, Zafirlukast and Zileuton. 66) Sedatives and hypnotics such as, for example, alpra Zolam, butalbital, chlordiazepoxide, diazepam, estazolam, flunitrazepam, flurazepam, lorazepam, midazolam, temazepam, triazolam, Zaleplon, Zolpidem, and Zopiclone. 67) Serotonin agonists such as, for example, 1-(4-bromo-2, 5-dimethoxyphenyl)-2-aminopropane, buspirone, m-chlo rophenylpiperazine, cisapride, ergot alkaloids, gepirone,

Feb. 25, 2016

8-hydroxy-(2-N,N-dipropylamino)-tetraline, ip Saperone, lysergic acid diethylamide, 2-methyl serotonin, meZacopride, Sumatriptan, tiaspirone, traZodone and Zacopride. 68) Serotonin antagonists such as, for example, amitryptiline, aZatadine, chlorpromazine, clozapine, cyproheptadine, dexfenfluramine, R(+)-a-(2,3-dimethoxyphenyl)-I-2-(4- fluorophenyl)ethyl-4-piperidine-methanold, lasetron, fen clonine, fenfluramine, granisetron, ketanserin, methysergide, metoclopramide, mianserin, ondansetron, risperidone, ritanserin, trimethobenzamide and tropisetron. 69) Steroid drugs such as, for example, alcometaSone, beclomethasone, beclomethasone dipropionate, betametha Sone, budesonide, butiXocort, ciclesonide, clobetasol, deflazacort, diflucortolone, desoxymethasone, dexametha sone, fludrocortisone, flunisolide, fluocinolone, flu ometholone, fluticasone, fluticaSone proprionate, hydrocorti Sone, methylprednisolone, mometasone, nandrolone decanoate, neom-cin Sulphate, prednisolone, rimesolone, rofileponide, triamcinolone and triamcinolone acetonide. 70) Sympathomimetic drugs such as, for example, adrena line, dexamfetamine, dipirefin, dobutamine, dopamine, dopexamine, isoprenaline, noradrenaline, phenylephrine, pseudoephedrine, tramaZoline and Xylometazoline. 71) Nitrates such as, for example, glyceryl trinitrate, isosor bide dinitrate and isosorbide mononitrate.

72) Skin and mucous membrane agents such as, for example, bergapten, isotretinoin and methoXSalen. 73) Smoking cessation aids such as, for example, bupropion, nicotine and Varenicline.

74) Drugs for treatment of Tourette's syndrome such as, for example, pimozide. 75) Drugs for treatment of urinary tract infections such as, for example, darifenicin, oxybutynin, propantheline bromide and tolteridine.

76) Vaccines. 0105 77) Drugs for treating vertigo such as, for example, betahistine and meclizine. 78) Therapeutic proteins and peptides such as acylated insu lin, glucagon, glucagon-like peptides, exendins, insulin, insu lin analogues, insulinaspart, insulin detemir, insulin glargine, insulin glulisine, insulin lispro, insulin Zinc, isophane insu lins, neutral, regular and insoluble insulins, protamine Zinc insulin, antibodies and antibody fragments. 79) Anticancer agents such as, for example, anthracyclines, doxorubicin, idarubicin, epirubicin, methotrexate, taxanes, paclitaxel, docetaxel, cisplatin, vinca alkaloids, Vincristine and 5-fluorouracil.

80) Pharmaceutically acceptable salts orderivatives of any of the foregoing. 0106. It should be noted that medicaments listed above under a particular indication or class may also find utility in other indications. A plurality of medicaments can be employed in the practice of the present invention. A drug delivery system according to the invention may also be used to deliver combinations of two or more different medica mentS.

0107. In one embodiment of the invention the medicament or combination of medicaments are suitable for the treatment of a respiratory disorder. In one embodiment the respiratory disorder is asthma or COPD.

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0108. In one embodiment the pharmaceutically active material is selected from a long-acting muscarinic antagonist and/or long-acting beta-adrenoceptor agonist and/or an inhaled corticosteroid. 0109. In one embodiment the medicament is selected from budesonide, formoterol fumarate dihydrate, tiotropium, flu ticasone propionate, salmeterol Xinafoate, Vilanterol trifena tate, umeclidinium bromide, glycopyrronium bromide or indacaterol maleate. 0110. In one embodiment the pharmaceutically active material is glycopyrronium bromide. In one embodiment the pharmaceutically active material is a combination of glyco pyrronium bromide and indacaterol maleate. 0111. In one embodiment the medicament is selected from budesonide and formoterol fumarate dehydrate. In one embodiment the medicament is selected from fluticaSone pro pionate and salmeterol Xinafoate. In one embodiment the medicament is selected from fluticaSone propionate and Vilanterol trifenatate. In one embodiment the medicament is selected from umeclidinium bromide and vilanterol trifena tate.

Containers and Inhalation Devices

0112. It is another aim of the present invention to provide a container comprising conditioned taurine or a composition comprising conditioned taurine. Containers which are Suit able for use in the present invention include either a bulk storage container, Such as a multi-dose reservoir for a dry powder inhaler, or unit dose containers such as a capsule or a blister. The capsule may be formed from various materials e.g. gelatine, cellulose derivatives such as hydroxypropyl methylcellulose (HPMC) or hydroxypropylcellulose (HPC), starch, starch derivatives, chitosan or synthetic plastics, while the blister may be provided in the form of a blister pack or blister strip. 0113 Containers which are also considered suitable for use in the present invention include pMDI canisters.

Administration

0114. In a further aspect of the present invention, the con ditioned taurine or a composition comprising conditioned taurine, suitable for inhalation, are preferably administered via a dry powder inhaler (DPI). In a dry powder inhaler, the dose to be administered is stored in the form of a non-pres Surized dry powder and, on actuation of the inhaler the par ticles of the powder are expelled from the device in the form of a cloud offinely dispersed particles that may be inhaled by the patient. 0115 Dry powder inhalers can be “passive' devices in which the patient’s breath is the only source of gas which provides a motive force in the device. Examples of “passive” dry powder inhaler devices include the RotahalerTM and Dis cus/DiskhalerTM, the MonohalerTM, the GyroHalerTM Turbu halerTM and NovolizerTM. Alternatively, “active” devices may be used, in which a source of compressed gas or alternative energy source is used. Examples of Suitable active devices include AspirairTM and the active inhaler device produced by Nektar Therapeutics (as covered by U.S. Pat. No. 6.257.233). 0116. It is generally considered that different composi tions perform differently when dispensed using passive and active type inhalers. Passive devices create less turbulence within the device and the powder particles are moving more slowly when they leave the device. This leads to some of the

Feb. 25, 2016

metered dose remaining in the device and, depending on the nature of the composition, less de-agglomeration upon actua tion. However, when the slow moving cloud is inhaled, less deposition in the throat is often observed. In contrast, active devices create more turbulence when they are activated. This results in more of the metered dose being extracted from the blister or capsule and better de-agglomeration as the powder is subjected to greater shear forces. However, the particles leave the device moving faster than with passive devices and this can lead to an increase in throat deposition. 0117 Particular “passive' dry powder inhalers that may be mentioned herein are “passive' dry powder inhalation devices that are described in WO 2010/086285. Particularly, “active' dry powder inhalers that may be mentioned herein are referred to as Aspirair R inhalers and are described in more detail in WO 2001/00262, WO 2002/07805, WO 2002/89880 and WO 2002/89881. It should be appreciated, however, that conditioned taurine or a composition comprising conditioned taurine of the present invention can be administered with either passive or active inhaler devices. 0118. In another aspect of the present invention, the con ditioned taurine or a composition comprising conditioned taurine, suitable for inhalation, are preferably administered via a spray or aerosol device. Such as a pressurised metered dose inhaler (pMDI). The composition (whether in solution or Suspension) may be for pulmonary, nasal, buccal or topical administration, but preferably for pulmonary inhalation. 0119 The pMDI is dependent upon the propulsive force of a propellant system used in its manufacture to dispense the composition from the device in a form that may be inhaled by a patient. The propellant generally comprises a mixture of liquefied hydrofluorocarbons (HFAs) which are selected to provide the desired vapour pressure and stability of the for mulation. Propellants HFA 227 (1,1,1,2,3,3,3-heptafluoro propane) and HFA 134a (1,1,1,2-tetrafluoroethane) or mix tures thereofare currently the most widely used propellants in aerosol formulations for inhalation administration.

0120 Additional embodiments of the invention include the following: 0121 Conditioned taurine suitable for inhalation. 0.122 Conditioned taurine which is crystalline. I0123 Conditioned taurine as an inhalation excipient. 0.124. A pharmaceutical composition comprising condi tioned taurine.

0.125. A pharmaceutical composition comprising condi tioned taurine further comprising an amino acid. The amino acid may be selected from the group consisting of alanine, leucine, isoleucine, lysine, Valine, methionine or phenylala nine, in one embodiment leucine. The leucine may be present in an amount less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less 3%, less than 2%, less than 1% by weight based on the dry weight of the composition. 0.126 A pharmaceutical composition comprising condi tioned taurine further comprising a medicament or combina tions of medicaments.

I0127. A pharmaceutical composition of the invention wherein the taurine and at least one other component are co-spray-dried using the spray drying conditions effective to produce conditioned taurine. I0128. A pharmaceutical composition of the invention suit able for inhalation.

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0129. A pharmaceutical composition of the invention wherein the conditioned taurine acts as an excipient, carrier or diluent. 0130. A pharmaceutical composition of the invention where the amino acid is located on the surface of the condi tioned taurine. 0131 Conditioned taurine made by a spray-drying method comprising:

0132 (a) providing a feedstock comprising raw taurine in an aqueous solution or Suspension; and

0.133 (b) spray-drying the feedstock under conditions to create particles that demonstrate no significant net change in the Do (t20%) after 7 days of ambient storage and have a particle size (Do) of <20 um, but more preferably <10 um after 7 days of ambient storage.

0134. A further embodiment of the invention is a method for preparing conditioned taurine comprising:

0.135 (a) providing a feedstock comprising raw taurine in an aqueous solution or Suspension; and

0.136 (b) spray-drying the feedstock under conditions to create particles that demonstrate no significant net change in the Doo (t20%) after 7 days of ambient storage and have a particle size (Do) of <20 Lim, but more preferably <10 um after 7 days of ambient storage.

0137 A further embodiment is a method of the invention wherein the pH of the feedstock is between pH 1 and pH 7, in one embodiment between pH 3 and pH 5. 0138 A further embodiment is a method of the invention wherein the pH of the feedstock is acidic e.g. less than pH 5. in one embodiment equal to or less than pH4. Such as about pH4. A further embodiment is a method of the invention wherein the feedstock concentration of taurine is between 0.1% and 10%, in one embodiment between 1% and 5%. 0139 A further embodiment is a method of the invention wherein the feedstock concentration of taurine is less than 5%. Such as less than 4%. Such as less than 3%, such as less than 2%, such as about 1%. 0140. A further embodiment is a method of the invention wherein the feedstock temperature is between 0.1° C. and 100° C., in one embodiment between 20° C. and 70° C. 0141. A further embodiment is a method of the invention wherein the feedstock temperature is less than 70° C., such as less than 60°C., such as less than 50° C., such as less than 40° C. Such as less than 30° C. 0142. A further embodiment is a method of the invention wherein the outlet temperature of the spray drying apparatus is between 50° C. and 120° C., in one embodiment between 60° C. and 100° C. 0143 A further embodiment is a method of the invention wherein the outlet temperature is less than 100° C., in one embodiment less than 90° C., in one embodiment less than 80°C., still in one embodiment less than 70° C., such as about 60° C. 0144. A further embodiment is a method of the invention wherein the Tsits ratio is between 2.00x10 and 2.75x 1O 0145 A further embodiment is a method of the invention for preparing conditioned taurine wherein the conditioned taurine particles have a particle size (Do) that remain below 20 um after 7 days of ambient storage post spray drying. 0146 A further embodiment is a method of the invention used to make a composition comprising taurine which further comprises an amino acid, e.g. selected from the group con

Feb. 25, 2016

sisting of alanine, leucine, isoleucine, lysine, Valine, methion ine or phenylalanine, in one embodiment leucine. 0147 A further embodiment is a method of the invention used to make a composition comprising taurine which further comprises a medicament or combinations of medicaments. 0.148. A further embodiment is a container comprising:

0.149 (a) conditioned taurine; or 0.150 (b) a composition comprising conditioned taurine

0151. The container may be a reservoir for a dry powder inhaler, a blister or a capsule. In one embodiment the con tainer is ablister such as a foil blister. 0152 Conditioned taurine having a moisture content of less than 2% by weight, optionally less than 1% by weight, optionally less than 0.5% by weight of conditioned taurine. 0153. Optionally the composition further comprises leu cine and a medicament or combinations of medicaments. The composition may be a powder.

EXAMPLES

0154 The following examples are provided to illustrate the invention but should not be construed as limiting the invention.

Example 1

Experimental Spray Drying Strategy

Zwitterionic Hypothesis:

0155 Astaurine is a Zwitterionic compound, it is believed that the Sulphur-hydyl group of the taurine becomes ionised (oxidation) with the proton being added to the amine group (reduction), in the feedstock and retains a charge even after drying. This leads to the material relaxing on storage which is believed to be the charged groups neutralising resulting in a conformatorial structural change. This conformatorial change causes agglomeration of the particles in the dry state, leading to a significant reduction in the aerosol performance. It is believed the neutralisation has a vitrification intermediate phase, which is the cause of the agglomeration (See FIG. 7).

Materials:

0156 Raw taurine was obtained from Sigma-Aldrich Chemicals (The old brickyard, New road, Gillingham, Dor set, SP8 4XT). Sodium Hydroxide, hydrochloric acid and citric acid were obtained from Fisher Scientific (Bishop Meadow Road, Loughborough, LE11 5RG).

Spray Drying Strategy:

0157. The Taurine spray drying process was investigated by producing 24 batches with varying process and formula tion parameters (factors). These were:

0158 Drying Gas flow rate 0159 Atomisation gas flow rate 0.160 Feedstock pumping rate (0161 Outlet temperature 0162 Feedstock temperature 0.163 Feedstock concentration 0164. Feedstock pH and buffer/acid type

0.165. These process and formulation parameters (factors) examined also affect the Zwitterionic neutralisation process and the hypothesis behind them are discussed below. The

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values for the extremes and centre points (levels) for each of the factors were determined on well documented physical design limits for spray dryers.

Drying Gas Flow Rate Parameters and Rationale: 0166 a) Definition of the Operation Range 0167. The drying gas flow rates range were determined as being just high enough to maintain particles in the airstream during drying while allowing a particle to have sufficient residence time in the drying chamber to complete drying. A significant enough Velocity is required to maintain curvilinear flow through the equipment and prevent premature deposition of the particles in the drying chamber of transfer conduit before collection and classification in the cyclone. If the dry ing gas is too high, then the Velocity of the particles will be too high to have Sufficient time in the drying gas for complete evaporation of all of the water from the feedstock to occur, resulting in high residual moisture (often >5.0% w/w). If particles have high residual moisture, then they are liable to agglomerate strongly through capillary forces and if partial dissolution occurs, then Solid bridging will occur. For this investigation and for the VSD equipment, the lower limit is defined as 12.0 Kg-Hr' and the upper limit defined as 15.0 Kg-Hr' and the centre point was defined as 13.5 Kg-Hr'. 0168 b) Impact and Effect on the Zwitterionic Neutrali sation

0169. The drying gas is believed to affect the neutralisa tion process of the taurine’s Sulphur-hydryl group, impacting the physical stability. A lower drying gas flow, results in a lower drying gas velocity, which in turn lowers the velocity of droplets and resultant particles. The lower velocity causes a slower rate of evaporation and results in a longer time period for charge neutralisation, giving particles more stable form, preventing the storage agglomeration that has been observed.

Atomisation Gas Flow Rate Parameters and Rationale:

0170 0171 The atomisation gas flow rate range was chosen to reflect the lowest limit where particles of inhalation size range for a given nozzle are produced. The upper limit defined as giving dry particles and no significant decrease in the Dso of the resultant particles, at a given drying gas flow rate. At higher atomisation flow rates, droplets/particles possess too high velocity and therefore low residence time in the drying chamber, resulting in particles with high residual moisture (often >5.0% w/w). If particles have high residual moisture, then they are liable to agglomeration. In extreme case, too high atomisation gas causes collisions between droplets before complete drying, leading to agglomerates being formed. For this investigation and for the VSD equipment, the lower limit is defined as 12.0 Limin' and the upper limit defined as 18.0 L'min', the centre point was defined as 15.0 L'min'.

a) Definition of the Operation Range

0172 b) Impact and Effect on the Zwitterionic Neutrali sation

0173 The atomisation gas flow rate has been shown to have an impact on the physical stability of spray dried taurine. One theory attributed to this mechanism is that there is a high degree of interaction of the atomising gas, with the liquid, not just to form Small and uniform droplets, but to catalyse the neutralisation of the Zwitterionic charges, potentially through oxidation of the Sulphur-hydryl group of taurine.

Feb. 25, 2016

Feedstock Pumping Rate Parameters and Rationale: 0.174 a) Definition of the Operation Range 0.175. The feedstock pumping rates range was chosen to reflect the lowest limit where the production rate of product was high enough to obtain Sufficient material for analysis in a reasonable amount of time. While lower rates can be achieved, too low a feedrate would take an unreasonable amount of time to produce a batch and would have commer cial limitations. The upper level was defined as the feedrate at which, for a given drying and atomisation gas flow rate, the particles produced were not effectively dried due to oversatu ration of the drying gas resulting in particles with high residual moisture (often >5.0% w/w). If particles have high residual moisture, then they are liable to agglomeration. For this investigation and for the VSD equipment, the lower limit is defined as 1.5 mL/min' and the upper limit defined as 4.5 mL min', the centre point was defined as 3.0 mL'min'. 0176 b) Impact and Effect on the Zwitterionic Neutrali sation 0177. The feed rate controls the amount offeedstock in the drying chamber per unit time. Therefore, the feed rate has a direct effect on the drying capacity of the gas through altering the Saturation concentration of water, which in turn alters the drying kinetics of the system and resultant particles. A low feed rate would have a larger drying capacity margin for the drying gas resulting in faster drying and thus potentially leading to less physically stable particles.

Outlet Temperature Parameters and Rationale: 0.178 a) Definition of the Operation Range 0179 The outlet temperature range was chosen to reflect the lowest temperature at which dry particles (often <5.0% w/w moisture) are collected (for the centre-point values of feedstock flow rate, atomisation gas and drying gas flow rates). The upper temperature was defined as the boiling point of water, above which the kinetic rate of evaporation only slightly increases. For this investigation and for the VSD equipment, the lower limit is defined as 60° C. and the upper limit defined as 100°C., the centre point was defined as 80°C. 0180 b) Impact and Effect on the Zwitterionic Neutrali sation 0181. The outlet temperature defines the thermal gradient across the drying chamber and thus has a Subsequent impact on the drying rate. As discussed for the drying gas rationale, alonger time to evaporate the water and form aparticle results in a longer time to allow charge neutrality and the conforma torial change to occur.

Feed Stock Temperature Parameters and Rationale: 0182 a) Definition of the Operation Range 0183 The feedstock temperature range was determined as being as low as room temperature, essentially 20°C., with the highest temperature where vapour was being produced result ing in variable concentrations of the feedstock being estab lished throughout the run. With this in mind, 70° C. was chosen. 0.184 b) Impact and Effect on the Zwitterionic Neutrali sation 0185. The temperature of the feedstock during spray dry ing will also be investigated to access how the temperature affects the pKa of the sulphur-hydryl group. Theoretically, an increase in the temperature could increase the pKa of the sulphur-hydryl group from the current relatively low 1.49

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(henderson-hasselbalch(1908)). This would mean that less acidification and shorter drying times could be required to achieve the same level of physical stability at lower tempera tures. In addition, adding heat to the feedstock increases the thermal energy in the atomised droplet which leads to a Smaller thermal gradient and may increase the droplet drying kinetics to allow a particle to be dried quicker. As discussed in previous sections, it is hypothesised that the increased drying rate leads to a shorter time for charge neutralisation and thus physical instability on storage.

Feedstock Concentration Parameters and Rationale:

0186 a) Definition of the Operation Range 0187. The feedstock concentration range was chosen as it will affect the drying kinetics and resultant size/density of the produced particles. A minimum of 1.0% w/v is often used to give an efficient production rate, while having acceptable PSD span. Above 5.0% w/v. the particle size increases above the inhalation size range for most 2 fluid nozzles. Therefore, the lower concentration was defined as 1.0% w/v and the upper range defined as 5.0% w/v. The centre point was defined as 2.5% w/v. 0188 b) Impact and Effect on the Zwitterionic Neutrali sation

0189 The concentration of the feedstock could have sev eral impacts on the drying kinetics and resultant particle stability. As taurine's Sulphur-hydryl group is a strong acid, increasing the concentration of taurine would mean a reduc tion in the pH. At a certain concentration, the taurine would

Drying Batch Gas

1 5 2 3.5 3 3.5 4 5 5 2 6 2 7 3.5 8 5 9 3.5 10 3.5 11 5 12 2 13 5 14 3.5 15 2 16 5 17 2 18 5 19 3.5 2O 2 21 2 22 3.5 23 5

2 2 4

generate sufficient protons to establish itself at its isoelectric point. This is not so simple if one considers a drying droplet, which alters the concentration as water is lost. Therefore, the initial pH might not necessarily be the optimum. (0190. Feedstock Solution pH and Buffer/Acid Type Parameters and Rationale 0191 The pH of the feedstock and the acid used to modify the pH is believed to affect the taurine stability via the Zwit terionic theory and driving the molecule to the isoelectric

Outlet Feed Temperature Rate Temperature

100 4.5 70 1 Citrate 4.0 5 8O 4.5 70 1 NA 5.5 2

100 1.5 45 2.5 NA 5.5 5 100 3 2O 1 NA 5.5 2 8O 3 2O 1 HCI 4.0 8

100 3 45 5 Citrate 4.0 2 60 1.5 45 1 NaOH 7.0 8 60 3 70 2.5 NaOH 7.0 2 60 4.5 2O 2.5 Citrate 4.0 8 8O 3 70 5 Citrate 4.0 8

100 4.5 45 5 HCI 4.0 8 60 3 45 2.5 NA 5.5 8 8O 3 2O 5 NaOH 7.0 5

100 3 70 2.5 HCI 4.0 5 60 1.5 70 1 HCI 4.0 2 8O 4.5 45 2.5 HCI 4.0 2 60 4.5 70 5 NA 5.5 5 60 1.5 45 1 Citrate 4.0 5 60 1.5 2O 5 HCI 4.0 5 8O 1.5 2O 2.5 Citrate 4.0 2 8O 4.5 45 1 NaOH 7.0 5

100 4.5 2O 5 NaOH 7.0 2 8O 1.5 70 5 NA 5.5 8

100 1.5 70 2.5 NaOH 7.0 8

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point when in the feedstock solution. Acidifying the Solution should allow the taurine to neutralise the sulphur-hydryl groups charge by reaching the molecules isoelectric point, which is calculated to be at pH 4.0 (See FIG. 8). The type of acid to do this may be important too. If the acid boils attoo a low a boiling point, or is an azeotrope, the conjugate base and associated proton will be removed in the drying process before the particle is dried and charge neutralisation capabil ity will be lost. But the acid and thus its residual conjugate base must be pharmaceutically acceptable as a salt forming agent, have a strong enough dissociation constant (pKa) to require very small effective concentrations to be effective and a high melting/boiling point to not be lost during drying prematurely. 0.192 Therefore, although the values for limits and opera tion space defined in this investigation are specific to the VSD spray dryer, the experimental strategy can be said to cover the complete operation space for spray drying that can be trans lated and transposed onto any spray dryer model at any scale where these physical limits and constraints exist.

Batch Preparation:

0193 24 raw taurine samples were dissolved in an appro priate amount of Milli-Q water and sonicated. The pH of each sample was adjusted accordingly. The prepared feedstock Solutions were separately spray-dried using a VSD spray drier with a 0.5 mm, two-fluid nozzle using various combi nations of the process and formulation parameters Sum marised in Table 1.

Atomisation Flow Rate

Feedstock Concentration Buffer pH

Feedstock

Table 1 Summaries the various combinations of the process and formulation parameters analysed

(i) Particle Size Distribution Analysis:

0194 Particle size distributions of the 24 sample batches were measured by laser diffraction using a Sympatec HELOS and RODOS particle size analyser and ASPIROS dispersion unit (0.5 bar dispersion). A focal length corresponding to R4

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lens was used and each batch sample was run in triplicate in order to determine the average particle size. In this instance, the Do for each batch sample was derived from the diffrac tion data using in-built Sympatec software (WINDOX 5.0). 0.195 Out of the 24 sample batches analysed, only 8 sample batches (Table 2) were identified as forming condi tioned taurine and demonstrated a particle size distribution of D-10.0 um.

TABLE 2

Summarises the PSD (Don) R4 lens at T=0 and T-7 days

PSD R4 Doo PSD R4 Doo Mean Sample Mean (m) T=0 (m) T=7days

11 7.42 8.90 13 8.30 8.79 15 4.82 S.80 16 8.19 8.44 17 7.89 8.17 19 7.86 7.91 2O 6.51 7.34 23 6.62 6.89

0196) Table 2, highlights the change in the Doo using the R4 lens, from initial (T=0) to the 7 daytime point (T-7 days). All 8 samples show a small increase (+20%) in the Do between the initial and 7 day time point and consequently the absence of any agglomeration. 0.197 FIG. 1, which depicts a model response plot for all 24 sample batches produced, similarly demonstrates that only 8 have an acceptable PSD profile after 7 days of storage. Statistical analysis reveals that the model was highly signifi cant with an R=1.00 and significant P value of p-0.05, meaning the null hypothesis is rejected and that the param eters modelled are significantly affecting the agglomeration potential of the taurine. The parameters that govern the pro duction of conditioned taurine are feedstock concentration, feedstockpumping rate, drying gas flow rate and second/third order interactions between them.

0198 The joint factor tests indicate from the p-values cal culated (see FIG. 9), that all the factors tested are significant. 0199 Taurine can be produced in a form for inhalation that meets the particle size criteria and particle size stability pro vided the spray drying process is carefully controlled. The control of the parameters is used to allow Zwitterionic neu tralisation during drying, to prevent this occurring during storage resulting in agglomeration and loss of primary par ticles. The data verifies the hypothesis that Zwitterionic neu tralisation is the most likely mechanism responsible for agglomeration in the Solid state and that all of the process and formulation parameters tested in this investigation have an impact on this process. 0200 While the model and analysis are specific to the VSD, the full operation space of the dryers capability has been mapped. Therefore, it can be inferred that inhalation taurine produced on any spray dryer and at any scale will exhibit the same dependence on all the parameters and lever ages, which control the neutralisation of the Zwitterionic charge. It would be straightforward, for any person skilled in the art to map the operation space of a spray dryer and achieve a similar model, with the same level of interdependence of the factors on the production of conditioned taurine.

Feb. 25, 2016

(ii) Calculating the Ratio of Taurine Dried Per Unit Time During Spray Drying

0201 It has been determined that the inter-relationship between these parameters (feedstock concentration, feed stockpumping rate and drying gas flow rate) can be explained using the following expression, which calculates the amount of taurine being dried versus the amount of drying gas present, per unit time.

(CXR) Tkaid-ras = Solid: Gas WDG

Where:

0202 T. Mass of taurine per Volume of drying gas per unit time (AU) C-Feedstock Concentration (g mL) R-Feedrate (mL min') V, Volume of Drying Gas (gmin') 0203. It has been determined by experiment that processed taurine and conditioned taurine products can be produced by spray drying when the T ratios are between 2.000x 10 (smallest ratio) and 2.750x10 (largest ratio). The use of a more acidic feedstock is also a significant factor (though not essential) and allows a wider operation window of param eters to be used in the production of conditioned taurine. 0204 Furthermore, to demonstrate that the calculated ratios are applicable to any open loop spray dryer, extrapola tions to the Niro spray dryer are shown as exemplification:

0205 Smallest ratio=3.529x10 0206 Largest ratio=2.118x10

0207. These calculated ratios fall within the range of the VSD spray dryer ratios. 0208 FIG. 2 depicts a visual variability chart showing the spread of the acceptable batches (i.e. conditioned taurine) produced as a function of the Tratios and indicates the relatively even spread across the theoretically operation range for the VSD spray dryer. Furthermore, the theoretical Niro spray dryer parameters are also seen to fall within the VSD operational range. 0209 FIG. 3 demonstrates the strong relationship of the conditioned taurine batches which obeys a quadratic relation ship with the Do of the PSD after 7 days. Therefore, a batch of any inhalable PSD that is stable i.e. conditioned can be made on any spray dryer at any scale using the quadratic equation defined below. Rearranging the equation will give an appropriate t-ratio which can then be used to select the appro priate drying gas, feed rate and concentration for that dryer based on its functional operation parameter ranges.

Where:

X=T-Ratio

A=6.8

B=3450.4

US 2016/005 1473 A1

0210 0211. Thermogravimetric analysis (TGA) determines the changes in sample weight in relation to change in tempera ture. This technique is used to examine the weight loss due to the removal of water upon heating and gives an assessment of the moisture content of the spray dried taurine samples.

(iii) Thermogravimetric Analysis:

TABLE 3

Summarises the equipment and method used

Equipment PerkinElmer TGA 5000 Starting Temperature 25o C. End Temperature 200° C. Heating Rate 10° C./min

0212 FIG. 4 illustrates the moisture content for each sample at the initial time point, T=0. All samples were below 0.2% w/w moisture.

0213 FIG. 5 illustrates the moisture content for each sample at the 7 day time point, T-7. All samples were below 0.2% w/w moisture, with the exception of sample batch 21 which measured 0.45% w/w moisture. In some instances the results obtained gave a negative weight loss. This was attrib uted to the balance drift in conjunction with the very small weight loss experienced and these results were Subsequently reported as a Zero-weight loss. 0214 Spray drying raw taurine, irrespective of the spray drying conditions used, resulted in spray-dried taurine dem onstrating very low moisture content (0.2% w/w in compari son to spray-dried trehalose, which is typically between 3% and 5% w/w). Furthermore, there was no significant change in moisture content during storage.

(iv) Differential Scanning Calorimetry

0215 Differential Scanning calorimetry (DSC) is a thermo-analysis technique in which the difference in the amount of heat required to increase the temperature of a sample and reference is measured as a function of tempera ture. This technique is used to assess the glass Transition temperatures (Tg) and melting characteristics of the spay dried samples. 0216 FIG. 6 illustrates a DSC graph depicting spray-dried taurine, exemplified with Sample 2 data. 0217. A glass transition temperature was not observed for any of the samples analysed, indicating that, irrespective of the spray drying conditions used, a transition from an amor phous form to crystalline does not occur, therefore the samples are produced in the crystalline form. The majority of samples examined demonstrated a melting point at approxi mately 333°C., with the lowest observed melting point seen at approximately 325°C.

Example 2

Materials

0218. Raw taurine and L-Leucine were obtained from Sigma-Aldrich Chemicals (The old brickyard, New road, Gillingham, Dorset, SP84XT). Trehalose was obtained from Ferro Pfanstiehl and Salbutamol sulphate was obtained from Cambrex Pharmaco.

Feb. 25, 2016

Preparation of Salbutamol Trehalose/L-Leucine Samples:

0219 Salbutamol sulphate (1% w/w), raw taurine OR tre halose (98.5% w/w) and L-Leucine (0.5% w/w) samples were dissolved in Milli-Q-water (800 ml) and sonicated. The pre pared feedstock Solutions were separately spray-dried using the Niro Mobile Minor X3000 with a 0.5 mm, two-fluid nozzle, according to the parameters outlined below in Table 4 and 5:

Sulphate/Taurine OR

Time PSD

Sample Parameters Storage Point Do Dso Doo

Tre? Leu Process A O 0.73 1.65 3.44 Sal Ambient 24 h 0.82 2.27 245.71

25o C. 24 h NA NA NA 50% RH

Tau Leu Process B O 0.75 1.75 3.86 Sal Ambient 24 O.75 1.74 3.80

25o C. 24 h 0.76 1.79 4.03 50% RH

TrefLeuf Process B O 0.72 1.59 3.20 Sal Ambient 24 O.94 75.8O 279.99

25o C. 24 h NA NA NA 50% RH

Table 4 Summarises the PSD R4 lens at T=0 and T=24 0220 Process A is a spray drying process using appropri ate spray drying conditions specific to the Niro Mobile Minor X3000 for producing optimal trehalose particles suitable for inhalation. It should be noted that these conditions can be modified by a person skilled in the art to ensure that trehalose particles suitable for inhalation are produced regardless of the spray drying machine used. 0221 Process B is a spray drying process using appropri ate spray drying conditions specific to the Niro Mobile Minor X3000 for producing optimal taurine particles, namely con ditioned taurine, Suitable for inhalation. These conditions can also be modified depending on the spray drying machine used.

TABLE 5

Summarises the spray drying parameters for Process A and Process B

Process Conditions Used

Component Parameters Process A Process B

Drying Gas Pressure 30 +/- 5.0 mm Wg Outlet 90.0° C. +f-3.0°C. 60.0° C. +f-3.0°C. Temperature Inlet 160.0°C. +f-3.0°C. 120.0° C. +f-3.0°C. Temperature

Feedstock Temperature 20.0° C. +f- 5.0°C. 50.0° C. +f- 5.0°C. Concentration 2.5% ww.

Atomisation Flow Rate 150 +/- 10 L min 200 +/- 10 L min' Gas Pressure 1.6 +/- 0.2 bar 3.94 +/- 0.2 bar

0222 Table 4 demonstrates that storage of Tre/Leu/Sal samples, processed under either “A” or “B” conditions and stored at 25°C./50% RH resulted in extreme agglomeration (represented by an N/A) due to an uptake of moisture result ing in total physical loss of primary particles e.g. agglomera tion induced through amorphous crystallisation. Only Tau/ Leu/Salsamples (FIG. 16) stored at 25°C/50% RH (process

US 2016/005 1473 A1

B) resulted in measurable PSD values. Furthermore these values (Do, Dso and Doo) were all <10 Jum.

Example 3

Preparation of Glycopyrronium Bromide/Taurine/L-Leucine Samples

0223 Glycopyrronium bromide (1.0% w/w), raw taurine (96.5% w/w) and L-leucine (2.5% w/w) samples were dis solved in Milli-Q water (60 mL) and sonicated. The prepared feedstock solution was spray dried using a laboratory spray dryer using a 0.5 mm, two fluid nozzle, 48.0 L 'min' atomi sation flow rate, 25.5 kg hr' drying gas flow rate, 60.0° C. outlet temperature and 5.0 gmin' feed rate. Spray drying parameters identified as appropriate for producing taurine particles suitable for inhalation.

Preparation of Glycopyrronium Bromide/Trehalose/L-Leucine Samples: 0224 Glycopyrronium bromide (1.0% w/w), raw treha lose dihydrate (89.0% w/w in the dried product) and L-leu cine (10.0% w/w) samples were dissolved in Milli-Q water (100 mL) and sonicated. The prepared feedstock solution was spray dried using a laboratory spray dryer using a 0.5 mm, two fluid nozzle, 42.0 L'min' atomisation flow rate, 18.0 kg hr' drying gas flow rate, 70.0° C. outlet temperature and 2.0 gmin' feed rate. Spray drying parameters identified as appropriate for producing taurine particles Suitable for inha lation.

Conditioning of Samples

0225. The taurine based formulation was stored in an open jar at ambient conditions overnight to condition the samples prior to analysis. 0226. The trehalose based formulation was stored in a sealedjar under low humidity (<5% RH) prior to analysis. 0227 Each formulation was assessed for PSD, KF and assay/content at the initial time point. For the taurine sample this corresponds to the powder after storage in an openijarat ambient conditions overnight. Fortrehalose this corresponds to the powder after storage overnight in a sealedjar under low humidity (<5% RH).

Formulation

Condition

glycopyrronium bromide

glycopyrronium bromide

Feb. 25, 2016

0228. Each formulation was then assessed for PSD and drug content after 24 hours storage open at a constant relative humidity (% RH) of 53% RH and 23+3° C.

Particle Size Distribution (PSD) 0229 Particle size distributions of the samples were mea sured by laser diffraction using a Sympatec HELOS and RODOS particle size analyser and ASPIROS dispersion unit (1.0 bar dispersion). A focal length corresponding to R4 lens was used and each batch sample was run in triplicate in order to determine the average particle size. In this instance, the Doo for each batch sample was derived from the diffraction data using in built Sympatec software (WINDOX 5.0).

Moisture Content by Karl Fischer (KF) 0230 Karl Fischer (KF) analysis is used to assess the water content of solid formulations using the Metrohm 774 Oven Sample Processor and 756KF Coulometer. The solid formulations were heated to a set temperature of 120.0°C. and titrated using the coulometer until no water is remaining in the sample. 10 mg of each powder was weighed and the samples assessed. This was performed on both the taurine and trehalose based formulations.

Aerosol Performance Testing 0231. The Fast Screening Impactor (FSI) was used to assess the aerosolisation properties of the powder. Each for mulation was assessed using gravimetric analysis, which involved filling a blister with the formulation (12.5+1.0 mg) and firing into the FSI. The mass of the powder evacuated from the blister and the mass collected on the fine fraction collector filter paper can then be calculated to evaluate how well the formulation is aerosolised. Water was used as the diluent for the insert.

Drug Content Assay

0232. The drug content of the taurine and trehalose based formulations were assessed using High Performance Liquid Chromatography (HPLC) at the initial time point and after 24 hours to assess the chemical stability of the formulations. 0233 All data is summarised in table 6.

Drug %

Mean Mean Mean Assay FPF D10 DSO D90 (% <5 Im KF

Time point (Lm) (Lm) (Lm) Nominal) t = 0 (% w/w)

Initial O.73 1.6S 3.43 103.1 70.2 2.59

24 hours at No result - solid 91.2

53% RH compact formed, 27 days at mechanical force ambient required to breakup

compact Initial O.76 1.79 402 100.7 40.3 O41

24 hours at 0.77 1.87 4.27 98.6

53% RH

27 days at O.77 1.85 423 ambient

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Table 6 Summarises the data for glycopyrronium bromide T=0, 24 hours and 27 days 0234 Table 6 demonstrates that both taurine and trehalose based formulations are aerosolisable and respirable at the initial time point. 0235. After 24 hours storage at 53% RH the trehalose formulation has agglomerated and is no longer respirable, a PSD assessment was not able to be performed due to the formation of a solid compact. Additionally, the drug content dropped from 103% of nominal to 91% of nominal, indicating this is not chemically stable. Whereas, after 24 hours storage at 53% RH the taurine formulation has remained respirable (D-10 um), and is chemically stable. After 27 days storage at ambient conditions the taurine particles remain respirable and aerosolisable.

Example 4

Preparation of Salbutamol Sulphate/Taurine/L-Leucine Samples

0236 Salbutamol sulphate (1.0% w/w), raw taurine (96. 5% w/w) and L-leucine (2.5% w/w) samples were dissolved in Milli-Q water (60 mL) and sonicated. The prepared feed stock solution was spray dried using a spray dryer using a 0.5 mm, two fluid nozzle, 48.0 L'min' atomisation flow rate, 25.5 kg hr' drying gas flow rate, 60.0°C. outlet temperature and 5.0 gmin' feed rate. Spray drying parameters identified as appropriate for producing taurine particles Suitable for inhalation. 0237. The taurine based formulation was stored in an open

jar at ambient conditions overnight to condition the samples. 0238. The formulation was assessed for PSD, KF and assay/content at the initial time point. 0239. The formulation was then assessed for PSD and drug content after 24 hours storage open at a constant relative humidity (% RH) of 53% RH and 23+3° C.

Particle Size Distribution (PSD) 0240 Particle size distributions of the samples were mea sured by laser diffraction using a Sympatec HELOS and RODOS particle size analyser and ASPIROS dispersion unit (1.0 bar dispersion). A focal length corresponding to R4 lens was used and each batch sample was run in triplicate in order to determine the average particle size. In this instance, the Do for each batch sample was derived from the diffraction data using in built Sympatec software (WINDOX 5.0).

Moisture Content by Karl Fischer (KF) 0241 Karl Fischer (KF) analysis is used to assess the water content of solid formulations using the Metrohm 774 Oven Sample Processor and 756KF Coulometer. The solid formulations were heated to a set temperature of 120.0°C. and titrated using the coulometer until no water is remaining in the sample. 10 mg of each powder was weighed and the samples assessed.

Aerosol Performance Testing 0242. The Fast Screening Impactor (FSI) was used to assess the aerosolisation properties of the powder. Each for mulation was assessed using gravimetric analysis, which involved filling a blister with the formulation (12.5+1.0 mg) and firing into the FSI. The mass of the powder evacuated from the blister and the mass collected on the fine fraction

Feb. 25, 2016

collector filter paper can then be calculated to evaluate how well the formulation is aerosolised. Water was used as the diluent for the insert.

Drug Content Assay

0243 The drug content of the taurine based formulation was assessed using High Performance Liquid Chromatogra phy (HPLC) at the initial time point and after 24 hours to assess the chemical stability of the formulation. 0244 All data is summarised in Table 7.

Drug % For- Mean Mean Mean Assay FPF KF mulation Time D10 DSO D90 (% <5 m (% Condition point (Lm) (Lm) (Lm) Nominal) t = 0 wiw)

Taurine, Initial O.77 1.87 4.26 97.9 42.O O.S Salbu- 24 hours O.78 1.92 4.38 99.4 tamol at sulphate 53% RH

26 days at 0.78 1.92 4.38 ambient

Table 7 Summarises the data for salbutamol sulphate T=0 and T=24 hours

0245 Table 7 demonstrates that the taurine based formu lation is aerosolisable and respirable at the initial time point. After 24 hours storage at 53% RH the taurine formulation remains respirable (DS10 um) and chemically stable. After 26 days at Storage at ambient conditions the taurine formula tion remains respirable and aerosolisable.

Example 5

Preparation of Sumatriptan Succinate/Taurine/L-Leucine Samples

0246 Sumatriptan succinate (1.0% w/w), raw taurine (96. 5% w/w) and L-leucine (2.5% w/w) samples were dissolved in Milli-Q water (60 mL) and sonicated. The prepared feed stock solution was spray dried using a spray dryer using a 0.5 mm, two fluid nozzle, 48.0 L 'min' atomisation flow rate, 25.5 kg hr' drying gas flow rate, 60.0°C. outlettemperature and 5.0 gmin' feed rate. Spray drying parameters identified as appropriate for producing taurine particles Suitable for inhalation.

0247 The taurine based formulation was stored in an open jar at ambient conditions overnight to condition the samples. 0248. The formulation was assessed for PSD, KF and assay/content at the initial time point. 0249. The formulation was then assessed for PSD and drug content after 24 hours storage open at a constant relative humidity (% RH) of 53% RH and 23+3° C.

Particle Size Distribution (PSD)

0250 Particle size distributions of the samples were mea sured by laser diffraction using a Sympatec HELOS and RODOS particle size analyser and ASPIROS dispersion unit (1.0 bar dispersion). A focal length corresponding to R4 lens was used and each batch sample was run in triplicate in order to determine the average particle size. In this instance, the Doo for each batch sample was derived from the diffraction data using in built Sympatec software (WINDOX 5.0).

US 2016/005 1473 A1 17

Moisture Content by Karl Fischer (KF) 0251 Karl Fischer (KF) analysis is used to assess the water content of solid formulations using the Metrohm 774 Oven Sample Processor and 756KF Coulometer. The solid formulations were heated to a set temperature of 120.0°C. and titrated using the coulometer until no water is remaining in the sample. 10 mg of each powder was weighed and the samples assessed.

Aerosol Performance Testing 0252. The Fast Screening Impactor (FSI) was used to assess the aerosolisation properties of the powder. Each for mulation was assessed using gravimetric analysis, which involved filling a blister with the formulation (12.5+1.0 mg) and firing into the FSI. The mass of the powder evacuated from the blister and the mass collected on the fine fraction collector filter paper can then be calculated to evaluate how well the formulation is aerosolised. Water was used as the diluent for the insert.

Drug Content Assay

0253) The drug content of the taurine based formulations was assessed using ultraviolet (U.V.) 0254 analysis at the initial time point and after 24 hours to assess the chemical stability of the formulation.

For- Mean Mean Mean Drug FPF mulation Time D10 D50 D90 Assay (% <5 m Condition point (Lm) (Lm) (Lm) Nominal) t = 0 KF

Taurine, Initial O.77 1.89 431 97.0 S3.9 O.48 Suma- 24 hours O.78 1.94 4.43 93.8 triptan at Succinate 53% RH

Feb. 25, 2016

-continued

% For- Mean Mean Mean Drug FPF mulation Time D10 D50 D90 Assay (% <5 m Condition point (Lm) (Lm) (Lm) Nominal) t = 0 KF

26 days at 0.78 1.92 4.39 ambient

Table 8 Summarises the data for Sumatriptan succinate T-0 and T-24 hours 0255 Table 8 demonstrates that the taurine based formu lation is aerosolisable and respirable at the initial time point, with Sumatriptan Succinate present. After 24 hours storage at 53% RH the taurine formulation remains aerosolisable and respirable (Doo<10 um) and chemically intact. After 26 days at storage at ambient conditions the taurine formulation remains respirable and aerosolisable. Dose Ranging Study Preparation of Salbutamol Sulphate/Taurine/L-Leucine Samples: 0256 Salbutamol sulphate, raw taurine and L-leucine samples were dissolved in the ratios detailed in Milli-Q water (60 mL) and sonicated. The prepared feedstock solution was spray dried using a spray dryer using a 0.5 mm, two fluid nozzle, 48.0 Liminatomisation flow rate, 25.5 kg hr' dry ing gas flow rate, 60.0° C. outlet temperature and 5.0 gmin' feed rate. Spray drying parameters identified as appropriate for producing taurine particles suitable for inhalation. 0257 The taurine based formulation was stored in an open jar at ambient conditions overnight to condition the samples. 0258. The formulations were assessed for PSD, KF and assay/content at the initial time point. 0259. The formulations was then assessed for PSD and drug content after 24 hours storage open at a constant relative humidity (% RH) of 53% RH and 23+3° C.

TABLE 9

Formulation composition and data for salbutamol Sulphate at a range of compositions T = 0 and T = 24 hours

Formulation Condition

Taurine 96.5% wiw, eucine

.0% wiw Taurine 87.5% wiw, Leucine

0.0% wiw Taurine

79.95% wiw, Leucine

7.55% ww Taurine

77.0% w/w, Leucine

2.5% w/w, drug 20.5% wiw

2.5% w/w, drug

2.5% w/w, drug

2.5% w/w, drug

Drug Mean Mean Assay D10 DSO Mean 96 FPF (%

Time point (m) (Lm) D90 (Lm) <5 um Nominal) KF

Initial 0.77 1.87 4.26 42.O 97.9 O.S 24 hours O.78 1.92 4.38 99.4 At 53% RH

Initial O.88 2.SS S.92 35.1 96.8 1.45 60 hours O.96 2.93 6.52 97.8 At 53% RH

Initial 1.02 3.21 6.93 39 97.7 1.27 24 hours 1.01 3.23 12.06 97.2 At 53% RH

Initial 1.26 3.87 7.75 33 97.0 O.15 24 hours 2.38 S4 94.59 99.6 At 53% RH

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TABLE 9-continued

Formulation composition and data for salbutamol Sulphate at a range of

Feb. 25, 2016

compositions T = 0 and T = 24 hours

Drug Mean Mean Assay

Formulation D10 DSO Mean 96 FPF (% Condition Time point (m) (Im) D90 (Lm) <5 um Nominal)

Taurine Initial 3.15 7.06 80.64 25 95.3 73.1% wiw, 24 hours 2.8 6.74 86.62 95.9 Leucine At 2.5% w/w, drug 53% RH 24.4% ww

0260 Table 9 shows that as the taurine concentration in the formulation decreases and the drug concentration increases the physically stabilising influence of taurine begins to dimin ish. 0261 There is no agglomeration of the powder when left at ambient overnight and at 53% RH (21+3°C.) for 24 hours at taurine concentrations of 96.5% w/w and 87.5% w/w. A Small amount of agglomeration is observed (n-1 rep) at 79.95% w/w taurine concentration. A larger amount of agglomeration is observed at taurine concentrations above 77.0% WFW.

Example 6

pMDI

Preparation of Salbutamol Samples:

0262 Salbutamol sulphate, raw taurine and L-leucine samples were dissolved in the ratios detailed in Table 10. Milli-Q water (60 mL) and sonicated. The prepared feedstock Solution was spray dried using a spray dryer using a 0.5 mm, two fluid nozzle, 48.0 L'min' atomisation flow rate, 25.5 kg hr' drying gas flow rate, 60.0°C. outlet temperature and 5.0 gmin' feed rate. Spray drying parameters identified as appropriate for producing taurine particles Suitable for inha lation.

0263. The taurine based formulation was stored in an open jar at ambient conditions overnight to condition the samples.

Sulphate/Taurine/L-Leucine

Preparation of Salbutamol/Taurine/L-Leucine Metered Dose Inhalers:

0264. Formulations as listed in table 10 were weighed into 19 mL Presspart aluminium canisters. A Bespak 35750 uL valve was crimped onto the cannister. P134a propellant was Subsequently filled through the valve using a Pamasol pres sure fill system. The filled can was placed into a Bespak Actuator with nominal orifice size of 0.42 mm.

Emitted Dose

0265 Prior to testing the MDI canister was placed in a Branson 8510 model Sonic bath for five minutes. Dose Uni formity Sampling Apparatus (DUSA) with a testing flow rate of 28.3 L'min' was used to assess the emitted dose from the MDI. Tenactuations from the MDI were fired into individual DUSA. The DUSA tubes were rinsed with fixed volumes of diluent to recover the salbutamol sulphate. Samples were

analysed using High Performance Liquid Chromatography (HPLC). The mean emitted dose was calculated as the aver age recovery from ten DUSA.

Particle Size Distribution of Emitted Dose

0266 Prior to testing the MDI canister was placed in a Branson 8510 model sonic bath for five minutes. The Next Generation Impactor (NGI) with a testing flow rate of 30 L'min' was used to assess the particle size distribution of the emitted dose from the MDI. Two actuations from the MDI were fired into the NGI. The MDI actuator, NGI throat and stages were washed with fixed volumes of diluent to recover the salbutamol Sulphate. Samples were analysed using High Performance Liquid Chromatography (HPLC). The Impactor Sized Mass (ISM, the sum of the recovered dose on stages 2 to the micro orifice collector of the NGI) was calculated as a function of the emitted dose (i.e. the ratio between the ISM and the sum of the ISM, throat and stage 1 deposition expressed as a percentage). The Mass Median Aerodynamic Diameter was determined.

Drug Content Assay 0267. The drug content of the salbutamol sulphate in pro pellant in the MDI canister was determined. Canisters were Submersed in liquid nitrogen to freeze propellant. An incision made in the valve shoulder allowed the propellant to sublime as the MDI equilibrated to room temperature. The canister and valve were rinsed with fixed volumes of diluent to recover the salbutamol Sulphate. Samples were analysed using High Performance Liquid Chromatography (HPLC).

Particle Size Distribution (PSD) Prior to Use in MDI Preparation 0268 Approximately 10 mg of formulation was dispersed in 0.2% lecithin in iso-octane and sonicated for 3 minutes using a Sonic probe. The sample was left to rest for 5 minutes then analysed for particle size distribution using the Malvern Mastersizer 2000, with a pump speed of 3000 rpm and an obscuration of 5-10%. 6 measurements were taken for each sample and the mean Do, Dso and D90 determined using the built in Malvern software. Particle Size Distribution (PSD)—after Use in MDI Prepara tion 0269 Prior to testing the MDI canister was placed in a Branson 8510 model Sonic bath for five minutes. Canisters were submersed in liquid nitrogen to freeze propellant. An incision made in the valve shoulder allowed the propellant to sublime as the MDI equilibrated to room temperature. For

US 2016/005 1473 A1

mulation was manually recovered from the canister. Approxi mately 10 mg of formulation was dispersed in 0.2% lecithin in iso-octane and Sonicated for 3 minutes using a Sonic probe. The sample was left to rest for 5 minutes then analysed for particle size distribution using the Malvern Mastersizer 2000, with a pump speed of 3000 rpm and an obscuration of 5-10%.

Feb. 25, 2016

TABLE 11

Formulation composition for salbutamol Sulphate in a range of MDI composition

Formulation

6 measurements were taken for each sample and the mean Formulation? per canister HFA 134a per D10, D50 and D90 determined using the built in Malvern "9" (mg) canister (mg) software. Taurine 87.5% w/w, Leucine 2.5% ww. 60 7350

Salbutamol Sulphate 10.0% w/w Visual Inspection of MDI Suspensions Taurine 73.1% w/w, Leucine 2.5% ww. 24 7350

Salbutamol Sulphate 24.4% w/w 0270. Formulations as listed in table 11 were weighed into Taurine 60 7350 plastic coated clear glass canisters. A continuous flow valve 90% w/w, Salbutamol Sulphate 10.0% w/w was crimped onto the canister. P134a propellant was subse- Taurine 100% ww 24 7350 quently filled through the valve using a Pamasol pressure fill system. Prior to testing the MDI canister was placed in a

TABLE 12

Formulation composition for salbutanol sulphate in a range of MDI compositions

Emitted Impactor Mean Mean Mean Mean Mean Mean Dose Sized Drug D10 D50 D90 D10 D50 D90 Mean Visible Mass (% Assay

Formulation Pre MDI Pre MDI Pre MDI Ex MDI Ex MIDI Ex MDI (Ig) Suspension of Emitted MMAD (% Condition (Lm) (Lm) (Lm) (Lm) (Lm) (m) (RSD, 9%) Duration (s) Dose) (Lm) Nominal)

Taurine 87.5% w/w, 1.O 2.9 6.5 1.O 2.9 6.6 SO.O 15 33.9 7.10 102 Leucine 2.5% w/w, (32.2) Salbutamol Sulphate 10.0% w/w Taurine 73.1% ww. 1.2 5.8 36.0 1.1 5.7 1S.O 813 >120 13.5 Not 102 Leucine 2.5% w/w, (13.0) Determined Salbutamol Sulphate 24.4% w/w Taurine 1.O 3.5 7.4 1.O 3.8 7.8 46.3 2O 33.8 7.39 100 90% w/w, (12.0) Salbutamol Sulphate 10.0% w/w Taurine 100% ww 1.1 2.9 5.9 1.1 2.8 5.5 15

Branson 8510 model sonic bath for five minutes. Each can ister was shaken for ten seconds and placed in front of a black background. Photographs were taken at 5 second intervals. Visual comparison of the photographs versus a clear glass canister allowed determination of the time where the majority of the formulation was no longer in Suspension. No creaming was visible for any of the Suspensions.

TABLE 10

Formulation composition for salbutamol Sulphate in a range of MDI compositions

Formulation

Formulation per canister HFA 134a per Condition (mg) canister (mg)

Taurine 87.5% w/w, Leucine 2.5% ww. 120 14700 Salbutamol Sulphate 10.0% w/w Taurine 73.1% w/w, Leucine 2.5% ww. 48 14700 Salbutamol Sulphate 24.4% w/w Taurine 120 14700

90% w/w, Salbutamol Sulphate 10.0% w/w Taurine 100% ww 48 14700

1. A method for preparing conditioned taurine, the method compr1S1ng

a conditioning step, wherein the conditioning step is a spray drying step, to produce taurine that: (a) demonstrates no significant net change in the Do

(+20%) after 7 days of ambient storage and (b) have a particle size Doo of <20 um, but more preferably <10 Lum after 7 days of ambient storage;

2. Conditioned taurine obtained by the method of claim 1. 3. The conditioned taurine according to claim 2, which is

suitable for inhalation.

4. The conditioned taurine according to claim 2, which is at least 95% crystalline.

5. A composition comprising conditioned taurine, in a dry powder form suitable for inhalation, wherein the dry powder form is prepared by spray drying.

6. A composition according to claim 5, further comprising an amino acid.

7. A composition according to claim 5 or 6, wherein the amino acid is selected from the group consisting of alanine, leucine, isoleucine, lysine, Valine, methionine or phenylala nine.

8. A composition according to claim 5 or 6, wherein the amino acid is leucine.

US 2016/005 1473 A1

9. A composition according to claim 8, wherein the leucine is present in an amountless than 10% by weight based on the dry weight of the composition.

10. A composition according to claim 5, further comprising a medicament.

11. A composition according to claim 10 in which the medicament is selected from budesonide, formoterol fuma rate dihydrate, tiotropium, fluticaSone propionate, salmeterol Xinafoate, Vilanterol trifenatate, umeclidinium bromide, gly copyrronium bromide or indacaterol maleate.

12. A composition according to claim 5, further comprising combinations of medicaments.

13. A composition according to claim 12 in which the combination of medicaments is selected from budesonide and formoterol fumarate dehydrate; fluticaSone propionate and salmeterol Xinafoate; fluticaSone propionate and Vilanterol trifenatate; and umeclidinium bromide and vilanterol trifena tate.

14. (canceled) 15. A method for preparing conditioned taurine, the

method comprising drying solubilised taurine, by spray drying with one or more of the following parameters:

(a) the pH of the feedstock to be spray dried is acidic e.g. less than pH 5, preferably equal to or less then pH 4, such as about pH 4;

(b) wherein the feedstock concentration is between 0.1% and 10%, more preferably between 1% and 5%;

20 Feb. 25, 2016

(c) the feedstock temperature is between 0.1° C. and 100° C., more preferably between 20° C. and 70° C.:

(d) the outlet temperature is between 50° C. and 120° C. more preferably between 60° C. and 100° C.:

(e) the Tits ratio is between 2.00x10 and 2.75x10 3.

16. A method for preparing conditioned taurine, the method comprising

drying solubilised taurine, by spray drying with one or more of the following parameters:

(a) the pH of the feedstock to be spray dried is less then pH 4.

(b) wherein the feedstock concentration is between 1% and 5%;

(c) the feedstock temperature is between 20°C. and 70° C.; (d) the outlet temperature is between 60° C. and 100° C.; (e) the Tits ratio is between 2.00x10 and 2.75x10

3.

17. A kit comprising a container which holds one selected from the group consisting of

(a) conditioned taurine; and (b) a composition comprising conditioned taurine which is prepared by spray drying. 18. A container according to claim 17 selected from the

group consisting of the reservoir for a dry powder inhaler, a blister and a capsule.

19. A method for preparing conditioned taurine, the method comprising a one-step spray drying process.

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